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2019 ESC Guidelines for the diagnosis and

management of chronic coronary syndromes

The Task Force for the diagnosis and management of chronic

coronary syndromes of the European Society of Cardiology (ESC)

Authors/Task Force Members: Juhani Knuuti* (Finland) (Chairperson),

William Wijns* (Ireland) (Chairperson), Antti Saraste (Finland), Davide Capodanno

(Italy), Emanuele Barbato (Italy), Christian Funck-Brentano (France),

Eva Prescott (Denmark), Robert F. Storey (United Kingdom), Christi Deaton

(United Kingdom), Thomas Cuisset (France), Stefan Agewall (Norway),

Kenneth Dickstein (Norway), Thor Edvardsen (Norway), Javier Escaned (Spain),

Bernard J. Gersh (United States of America), Pavel Svitil (Czech Republic),

Martine Gilard (France), David Hasdai (Israel), Robert Hatala (Slovak Republic),

Felix Mahfoud (Germany), Josep Masip (Spain), Claudio Muneretto (Italy),

Marco Valgimigli (Switzerland), Stephan Achenbach (Germany), Jeroen J. Bax

(Netherlands)

Document Reviewers: Franz-Josef Neumann (Germany) (CPG Review Coordinator), Udo Sechtem

(Germany) (CPG Review Coordinator), Adrian Paul Banning (United Kingdom), Nikolaos Bonaros

(Austria), He´ ctor Bueno (Spain), Raffaele Bugiardini (Italy), Alaide Chieffo (Italy), Filippo Crea (Italy),

* Corresponding authors: Juhani Knuuti, Department of Clinical Physiology, Nuclear Medicine and PET and Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-

20520 Turku, Finland. Tel: þ 358 500 592 998, Email: juhani.knuuti@tyks.ﬁ. William Wijns, The Lambe Institute for Translational Medicine and Curam, National University of

Ireland, Galway, University Road, Galway, H91 TK33, Ireland. Tel: þ 353 91 524411, Email: william.wyns@nuigalway.ie.

Author/Task Force Member Afﬁliations: listed in the Appendix.

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.

ESC entities having participated in the development of this document:

Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular

Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm

Association (EHRA), Heart Failure Association (HFA).

Councils: Council for Cardiology Practice.

Working Groups: Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation,

Thrombosis.

The content of these ESC Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be trans-

lated or reproduced in any form without written permission from the ESC. Permission 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@oxfordjournals.org).

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 recom-

mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-

aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diag nostic, 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.

European Heart Journal (2019) 00 ,1 71

ESC GUIDELINES

doi:10.1093/eurheartj/ehz425

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Martin Czerny (Germany), Victoria Delgado (Netherlands), Paul Dendale (Belgium),

Frank Arnold Flachskampf (Sweden), Helmut Gohlke (Germany), Erik Lerkevang Grove (Denmark),

Stefan James (Sweden), Demosthenes Katritsis (Greece), Ulf Landmesser (Germany), Maddalena Lettino

(Italy), Christian M. Matter (Switzerland), Hendrik Nathoe (Netherlands), Alexander Niessner (Austria),

Carlo Patrono (Italy), Anna Sonia Petronio (Italy), Steffen E. Pettersen (United Kingdom), Raffaele Piccolo

(Italy), Massimo Francesco Piepoli (Italy), Bogdan A. Popescu (Romania), Lorenz R €

aber (Switzerland),

Dimitrios J. Richter (Greece), Marco Rofﬁ (Switzerland), Franz X. Roithinger (Austria), Evgeny Shlyakhto

(Russian Federation), Dirk Sibbing (Germany), Sigmund Silber (Germany), Iain A. Simpson

(United Kingdom), Miguel Sousa-Uva (Portugal), Panos Vardas (Greece), Adam Witkowski (Poland),

Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these Guidelines are available on the

ESC website www.escardio.org/guidelines

For the Supplementary Data which include background information and detailed discussion of the data

that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/

10.1093/eurheartj/ehz425#supplementary-data

........................................................................ ............. ............. ............. .................. ..................................................................

Keywords Guidelines • chronic coronary syndromes • angina pectoris • myocardial ischaemia • coronary artery

disease • diagnostic testing • imaging • risk assessment • lifestyle modiﬁcations • anti-ischaemic drugs •

antithrombotic therapy • lipid-lowering drugs • myocardial revascularization • microvascular angina •

vasospastic angina •screening

Table of contents

1.Preamble ........................................................ 5

2.Introduction ..................................................... 7

2.1Whatisnewinthe2019Guidelines? .......................... 8

3. Patients with angina and/or dyspnoea, and suspected

coronaryarterydisease ............................................ 10

3.1 Basic assessment, diagnosis,and risk assessment . . . . . . . . . . . . . . 10

3.1.1Step1:symptomsandsigns .............................. 11

3.1.1.1Stablevs.unstableangina............................ 12

3.1.1.2 Distinction between symptoms caused by

epicardial vs. microvascular/vasospastic disease . . . . . . . . . . . . . 13

3.1.2 Step 2: comorbidities and other causes of symptoms . . . . . . 13

3.1.3Step3:basictesting ...................................... 13

3.1.3.1Biochemicaltests ................................... 13

3.1.3.2 Resting electrocardiogram and ambulatory

monitoring ................................................ 14

3.1.3.3 Echocardiography and magnetic resonance

imagingatrest ............................................. 14

3.1.3.4ChestX-ray ........................................ 15

3.1.4 Step 4: assess pre-test probability and clinical likelihood

ofcoronaryarterydisease .................................... 15

3.1.5Step5:selectappropriatetesting ......................... 16

3.1.5.1Functionalnon-invasivetests ........................ 16

3.1.5.2Anatomicalnon-invasiveevaluation ................. 17

3.1.5.3 Role of the exercise electrocardiogram . . . . . . . . . . . . . . 17

3.1.5.4Selectionofdiagnostictests ......................... 18

3.1.5.5 The impact of clinical likelihood on the selection

ofadiagnostictest ................................ ......... 18

3.1.5.6Invasivetesting ..................................... 19

3.1.6Step6:assesseventrisk ......................... ......... 21

3.1.6.1Definitionoflevelsofrisk ........................... 22

3.2Lifestylemanagement ........................................ 23

3.2.1 General management of patients with coronary artery

disease ....................................................... 23

3.2.2 Lifestyle modification andcontrol of risk factors . . . . . . . . . . 23

3.2.2.1Smoking ........................................... 23

3.2.2.2Dietandalcohol .................................... 24

3.2.2.3Weightmanagement ............................... 24

3.2.2.4Physicalactivity ..................................... 24

3.2.2.5Cardiacrehabilitation ............................... 24

3.2.2.6Psychosocialfactors ................................ 24

3.2.2.7Environmentalfactors .............................. 25

3.2.2.8Sexualactivity ...................................... 25

3.2.2.9Adherenceandsustainability ........................ 25

3.2.2.10Influenzavaccination............................... 25

3.3Pharmacologicalmanagement ................................ 26

3.3.1Anti-ischaemicdrugs .................................... 26

3.3.1.1Generalstrategy .................................... 26

3.3.1.2Availabledrugs ..................................... 26

3.3.1.3Patientswithlowbloodpressure .................... 29

3.3.1.4Patientswithlowheartrate ......................... 29

3.3.2Eventprevention ........................................ 30

3.3.2.1Antiplateletdrugs .................................. 30

3.3.2.2 Anticoagulant drugs in sinus rhythm . . . . . . . . . . . . . . . . . 30

3.3.2.3 Anticoagulant drugs in atrial fibrillation . . . . . . . . . . . . . . . 31

3.3.2.4Protonpumpinhibitors ............................. 31

3.3.2.5 Cardiac surgery and antithrombotictherapy . . . . . . . . . 31

3.3.2.6 Non-cardiac surgery and antithrombotic therapy . . . . 32

3.3.3 Statins and other lipid-lowering drugs . . . . . . . . . . . . . . . . . . . . 34

3.3.4 Renin-angiotensin-aldosterone system blockers . . . . . . . . . . 34

3.3.5Hormonereplacementtherapy .......................... 35

2ESC Guidelines

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3.4Revascularization ............................................ 35

4. Patients with new onset of heart failure or reduced left

ventricularfunction ....................... ......................... 36

5. Patients with a long-standing diagnosis of chronic coronary

syndromes ........................................................ 38

5.1 Patients with stabilized symptoms <1 year after an acute

coronary syndrome or patients with recent revascularization . . . . . 38

5.2 Patients >1 year afterinitial diagnosis or revascularization . . . . . 38

6. Angina without obstructive disease in the epicardial

coronaryarteries .................................................. 40

6.1Microvascularangina ........................................ 41

6.1.1Riskstratification ........................................ 41

6.1.2Diagnosis ............................................... 41

6.1.3Treatment .............................................. 41

6.2Vasospasticangina ........................................... 42

6.2.1Diagnosis ............................................... 42

6.2.2Treatment .............................................. 42

7. Screening for coronary artery disease in asymptomatic subjects . . . 43

8. Chronic coronary syndromes in specific circumstances . . . . . . . . . . . 44

8.1Cardiovascularcomorbidities ................................ 44

8.1.1Hypertension ........................................... 44

8.1.2 Valvular heart disease (including planned transcatheter

aorticvalveimplantation) ..................................... 44

8.1.3Afterhearttransplantation............................... 44

8.2Non-cardiovascularcomorbidities ........................... 45

8.2.1Cancer ................................................. 45

8.2.2Diabetesmellitus ........................................ 45

8.2.3Chronickidneydisease .................................. 46

8.2.4Elderly .................................................. 46

8.3Sex ......................................................... 46

8.4Patientswithrefractoryangina ............................... 47

9.Keymessages ................................................... 48

10.Gapsintheevidence ........................................... 49

10.1Diagnosisandassessment................................... 49

10.2Assessmentofrisk ......................................... 49

10.3Lifestylemanagement ...................................... 49

10.4Pharmacologicalmanagement .............................. 49

10.5Revascularization ........................................... 49

10.6Heartfailureandleftventriculardysfunction ................. 49

10.7 Patients with long-standing diagnosis of chronic

coronarysyndromes ............................................ 49

10.8 Anginawithout obstructive coronary artery disease . . . . . . . . . 49

10.9Screeninginasymptomaticsubjects ......................... 49

10.10Comorbidities ............................................ 50

10.11Patientswithrefractoryangina ............................. 50

11. 'What to do' and 'what not to do' messages from the

Guidelines ........................................................ 50

12.Supplementarydata ............................................ 54

13.Appendix ................................................ ...... 54

14.References .................................................... 55

Recommendations

2019Newmajorrecommendations ................................. 8

Changesinmajorrecommendations ............................... 10

Basic biochemistry testing in the initial diagnostic management

ofpatientswithsuspectedcoronaryarterydisease .................. 13

Resting electrocardiogram in the initial diagnostic management

ofpatientswithsuspectedcoronaryarterydisease .................. 14

Ambulatory electrocardiogram monitoring in the initial

diagnostic management of patients with suspected coronary

arterydisease ..................................................... 14

Resting echocardiography and cardiac magnetic resonance in

the initial diagnostic management of patients with suspected

coronaryarterydisease ............................................ 15

Chest X-ray in the initial diagnostic management of patients

withsuspectedcoronaryarterydisease ............................. 15

Use of diagnostic imaging tests in the initial diagnostic

management of symptomatic patients with suspected coronary

arterydisease ..................................................... 20

Performing exercise electrocardiogram in the initial diagnostic

management of patients with suspected coronary artery disease . . . . . 20

Recommendationsforriskassessment ............................. 22

Recommendationsonlifestylemanagement ........................ 25

Recommendations on anti-ischaemic drugs in patients with

chroniccoronarysyndromes ...................................... 29

RecommendationsforeventpreventionI ........................... 32

RecommendationsforeventpreventionII .......................... 35

General recommendations for the management of patients with

cnronic coronary syndromes and symptomatic heart failure

due to ischaemic cardiomyopathy and left ventricular systolic

dysfunction ....................................................... 37

Recommendations for patients with a long-standing diagnosis

ofchroniccoronarysyndromes .................................... 40

Investigations in patients with suspectedcoronary microvascular

angina . ......................................................... ... 42

Recommendations for investigations in patients with suspected vasospas-

ticangina ...................... .................................... 42

Recommendations for screening for coronary artery disease in

asymptomaticsubjects . ............................................ 43

Recommendations for hypertension treatment in chronic

coronarysyndromes .............................................. 44

Recommendations for valvular disease in chronic coronary

syndromes ........................................................ 44

Recommendations for active cancer in chronic coronary

syndromes ........................................................ 45

Recommendations for diabetes mellitus in chronic coronary

syndromes ........................................................ 45

Recommendations for chronic kidney disease in chronic

coronarysyndromes .............................................. 46

Recommendations for elderly patients withchronic

coronarysyndromes .............................................. 46

Recommendation for sex issues and chronic coronary

syndromes ........................................................ 47

Recommendations for treatment options for refractory angina . . . . . . 48

Recommendations:'whattodo'and'whatnottodo' ................ 50

List of tables

Table1Classesofrecommendations ................................ 6

Table2Levelsofevidence .......................................... 6

ESC Guidelines 3

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Table 3 Traditional clinical classification of suspected anginal

symptoms ........................... .............................. 12

Table 4 Grading of effort angina severity according to the

CanadianCardiovascularSociety ................................... 12

Table 5 Pre-test probabilities of obstructive coronary artery

disease in 15815 symptomatic patients according toage, sex,

and the nature of symptoms in a pooled analysis of contemporary

data .................................... ........................... 16

Table 6 Definitions of high event risk for different test modalities

in patientswith establishedchronic coronary syndromes . . . . . . . . . . . . 21

Table 7 Lifestyle recommendations for patients with chronic

coronarysyndromes. .............................................. 23

Table8Healthydietcharacteristics ................... .............. 24

Table 9 Treatment options for dual antithrombotic therapy in

combination with aspirin 75-100 mg daily in alphabetical order in

patients who have a high or moderate risk of ischaemic events,

anddonothaveahighbleedingrisk. ................................ 34

Table 10 Blood pressure thresholds for definition of hypertension

with different types of blood pressure measurement . . . . . . . . . . . . . . . . 44

Table 11 Potential treatment options for refractory angina and

summaryoftrialdata .............................................. 47

List of figures

Figure 1 Schematic illustration of the natural history of chronic

coronarysyndromes ............................................... 7

Figure 2 Approach for the initial diagnostic management of patients

with angina and suspected coronary artery disease . . . . . . . . . . . . . . . . . . 11

Figure 3 Determinants of clinical likelihood of obstructive coronary

arterydisease ..................................................... 17

Figure 4 Main diagnostic pathways in symptomatic patients

with suspected obstructive coronary artery disease . . . . . . . . . . . . . . . . . 18

Figure 5 Ranges of clinical likelihood of coronary artery disease

in which the test can rule-in or rule-out obstructive coronary

arterydisease ..................................................... 19

Figure 6 Comparison of risk assessments in asymptomatic

apparently healthy subjects (primary prevention) and patients with

established chronic coronary syndromes (secondary prevention) . . . . 21

Figure7ThefiveAsofsmokingcessation ........................... 24

Figure 8 Suggested stepwise strategy for long-term

anti-ischaemic drug therapy in patients with chronic coronary

syndromesandspecificbaselinecharacteristics ..................... 28

Figure 9 Decision tree for patients undergoing invasive coronary

angiography ....................................................... 36

Figure 10 Proposed algorithm according to patient types

commonly observed at chronic coronary syndrome outpatient

clinics ............................................................. 39

Abbreviations and acronyms

ABI Ankle-brachial index

ACE Angiotensin-converting enzyme

ACS Acute coronary syndrome(s)

ACTION A Coronary disease Trial Investigating Outcome

with Nifedipine gastrointestinal therapeutic system

AF Atrial ﬁbrillation

ARB Angiotensin receptor blocker

AUGUSTUS An Open-label, 2  2 Factorial, Randomized

Controlled, Clinical Trial to Evaluate the Safety of

Apixaban vs. Vitamin K Antagonist and Aspirin vs.

Aspirin Placebo in Patients With Atrial Fibrillation

and Acute Coronary Syndrome or Percutaneous

Coronary Intervention

BARI-2D Bypass Angioplasty Revascularization Investigation

2 Diabetes

BEAUTIFUL I

Inhibitor Ivabradine in Patients with Coronary

Artery Disease and Left Ventricular Dysfunction

b.i.d. Bis in die (twice a day)

BMI Body mass index

BP Blood pressure

b.p.m. Beats per minute

CABG Coronary artery bypass grafting

CAD Coronary artery disease

CAPRIE Clopidogrel vs. Aspirin in Patients at Risk of

Ischaemic Events

CASS Coronary Artery Surgery Study

CCB Calcium channel blocker

CCS Chronic coronary syndrome(s)

CFR Coronary ﬂow reserve

CHA

VASc

Cardiac failure, Hypertension, Age >_75

[Doubled], Diabetes, Stroke [Doubled] 

Vascular disease, Age 65 74 and Sex category

[Female]

CHD Coronary heart disease

CI Conﬁdence interval

CKD Chronic kidney disease

CMR Cardiac magnetic resonance

COMPASS Cardiovascular Outcomes for People Using

Anticoagulation Strategies

COURAGE Clinical Outcomes Utilizing Revascularization and

Aggressive Drug Evaluation

CPG Committee for Practice Guidelines

CRT Cardiac resynchronization therapy

CT Computed tomography

CTA Computed tomography angiography

CVD Cardiovascular disease

DAPT Dual antiplatelet therapy

DES Drug-eluting stent(s)

DHP Dihydropyridine

ECG Electrocardiogram

eGFR Estimated glomerular ﬁltration rate

ESC European Society of Cardiology

FAME 2 Fractional Flow Reserve versus Angiography for

Multivessel Evaluation 2

FFR Fractional ﬂow reserve

4ESC Guidelines

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FFR

Computed tomography-based fractional ﬂow

reserve

GEMINI-

ACS

A Study to Compare the Safety of Rivaroxaban

Versus Acetylsalicylic Acid in Addition to Either

Clopidogrel or Ticagrelor Therapy in Participants

With Acute Coronary Syndrome

GFR Glomerular ﬁltration rate

GLS Global longitudinal strain

GOSPEL Global secondary prevention strategies to limit

event recurrence after myocardial infarction

HbA1c Glycated haemoglobin

HF Heart failure

ICA Invasive coronary angiography

IMR Index of microcirculatory resistance

IMT Intima-media thickness

IONA Impact Of Nicorandil in Angina

iwFR Instantaneous wave-free ratio (instant ﬂow

reserve)

LAD Left anterior descending

LBBB Left bundle branch block

LDL-C Low-density lipoprotein cholesterol

LM Left main (coronary artery)

LV Left ventricular

LVEF Left ventricular ejection fraction

MI Myocardial infarction

MRA Mineralocorticoid receptor antagonist

NOAC Non-vitamin K antagonist oral anticoagulant

NT-proBNP N-terminal pro-B-type natriuretic peptide

OAC Oral anticoagulant

o.d. Omni die (once a day)

ORBITA Objective Randomised Blinded Investigation with

optimal medical Therapy of Angioplasty in stable

angina

PAD Peripheral artery disease

PCI Percutaneous coronary intervention

PCSK9 Proprotein convertase subtilisin-kexin type 9

PEGASUS-

TIMI 54

Prevention of Cardiovascular Events in Patients

with Prior Heart Attack Using Ticagrelor

Compared to Placebo on a Background of

Aspirin Thrombolysis in Myocardial Infarction 54

PET Positron emission tomography

PROMISE Prospective Multicenter Imaging Study for

Evaluation of Chest Pain

PTP Pre-test probability

RAS Renin-angiotensin system

RCT Randomized clinical trial

REACH Reduction of Atherothrombosis for Continued

Health

RIVER-PCI Ranolazine for Incomplete Vessel Revascularization

Post-Percutaneous Coronary Intervention

SCORE Systematic COronary Risk Evaluation

SCOT-

HEART

Scottish Computed Tomography of the HEART

SIGNIFY Study Assessing the Morbidity Mortality Beneﬁts

of the If Inhibitor Ivabradine in Patients with

Coronary Artery Disease

SPECT Single-photon emission computed tomography

VKA Vitamin K antagonist

1 Preamble

Guidelines summarize and evaluate available evidence with the aim of

assisting health professionals in proposing the best management

strategies for an individual patient with a given condition. Guidelines

and their recommendations should facilitate decision making of

health professionals in their daily practice. However, the final deci-

sions concerning an individual patient must be made by the responsi-

ble health professional(s) in consultation with the patient and

caregiver as appropriate.

A great number of guidelines have been issued in recent years by

the European Society of Cardiology (ESC), as well as by other soci-

eties and organizations. Because of their impact on clinical practice,

quality criteria for the development of guidelines have been estab-

lished in order to make all decisions transparent to the user. The rec-

ommendations for formulating and issuing ESC Guidelines can be

found on the ESC website (http://www.escardio.org/Guidelines-&-

Education/Clinical-Practice-Guidelines/Guidelines-development/

Writing-ESC-Guidelines). The ESC Guidelines represent the offi-

cial position of the ESC on a given topic and are regularly updated.

The ESC carries out a number of registries which are essential to

assess, diagnostic/therapeutic processes, use of resources and adher-

ence to Guidelines. These registries aim at providing a better under-

standing of medical practice in Europe and around the world, based

on data collected during routine clinical practice.

The guidelines are developed together with derivative educational

material addressing the cultural and professional needs for cardiolo-

gists and allied professionals. Collecting high-quality observational

data, at appropriate time interval following the release of ESC

Guidelines, will help evaluate the level of implementation of the

Guidelines, checking in priority the key end points defined with the

ESC Guidelines and Education Committees and Task Force members

in charge.

The Members of this Task Force were selected by the ESC,

including representation from its relevant ESC sub-specialty

groups, in order to represent professionals involved with the

medical care of patients with this pathology. Selected experts in

the field undertook a comprehensive review of the published evi-

dence for management of a given condition according to ESC

Committee for Practice Guidelines (CPG) policy. A critical evalua-

tion of diagnostic and therapeutic procedures was performed,

including assessment of the riskbenefit ratio. The level of evidence

and the strength of the recommendation of particular manage-

ment options were weighed and graded according to predefined

scales, as outlined in Tables 1and 2 .

The experts of the writing and reviewing panels provided declara-

tion of interest forms for all relationships that might be perceived as

ESC Guidelines 5

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real or potential sources of conflicts of interest. These forms were

compiled into one file and can be found on the ESC website (http://

www.escardio.org/guidelines). Any changes in declarations of interest

that arise during the writing period were notified to the ESC and

updated. The Task Force received its entire financial support from

the ESC without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of

new Guidelines. The Committee is also responsible for the

endorsement process of these Guidelines. The ESC Guidelines

undergo extensive review by the CPG and external experts. After

appropriate revisions the Guidelines are approved by all the

experts involved in the Task Force. The finalized document is

approved by the CPG for publication in the European Heart

Journal. The Guidelines were developed after careful considera-

tion of the scientific and medical knowledge and the evidence

available at the time of their dating.

Table 1 Classes of recommendations

ESC 2019

Classes of recommendations

Class I Evidence and/or general agreement

that a given treatment or procedure is

Is recommended or is indicated

Wording to use

Class III Evidence or general agreement that the

given treatment or procedure is not

useful/effective, and in some cases

may be harmful.

Is not recommended

Class IIb

established by evidence/opinion.

May be considered

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

Class II

Table 2 Levels of evidence

©ESC 2019

Level of

evidence A

Data derived from multiple randomized clinical trials

or meta-analyses.

Level of

evidence B

Data derived from a single randomized clinical trial

or large non-randomized studies.

Level of

evidence C

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

retrospective studies, registries.

6ESC Guidelines

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The task of developing ESC Guidelines also includes the crea-

tion of educational tools and implementation programmes for the

recommendations including condensed pocket guideline versions,

summary slides, booklets with essential messages, summary cards

for non-specialists and an electronic version for digital applications

(smartphones, etc.). These versions are abridged and thus, for

more detailed information, the user should always access to the

full text version of the Guidelines, which is freely available via the

ESC website and hosted on the EHJ website. The National

Societies of the ESC are encouraged to endorse, translate and

implement all ESC Guidelines. Implementation programmes are

needed because it has been shown that the outcome of disease

may be favourably influenced by the thorough application of clini-

cal recommendations.

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 or the patient's caregiver where appropriate and/or

necessary. It is also the health professional's responsibility to verify

the rules and regulations applicable in each country to drugs and devi-

ces at the time of prescription.

2 Introduction

Coronary artery disease (CAD) is a pathological process character-

ized by atherosclerotic plaque accumulation in the epicardial arteries,

whether obstructive or non-obstructive. This process can be modi-

fied by lifestyle adjustments, pharmacological therapies, and invasive

interventions designed to achieve disease stabilization or regression.

The disease can have long, stable periods but can also become unsta-

ble at any time, typically due to an acute atherothrombotic event

caused by plaque rupture or erosion. However, the disease is

chronic, most often progressive, and hence serious, even in clinically

apparently silent periods. The dynamic nature of the CAD process

results in various clinical presentations, which can be conveniently

Time

Cardiac risk (death, MI)

Higher risk with

insufficiently controlled

risk factors, suboptimal

lifestyle modifications

and/or medical therapy,

large area at risk of

myocardial ischaemia

Subclinical

phase

Recent diagnosis or

revascularization

Long-standing diagnosis

Lower risk with

optimally controlled risk

factors, lifestyle changes,

adequate therapy for

secondary prevention

(e.g. aspirin, statins, ACE

inhibitors) and

appropriate

revascularization

Revascularization

12 month

post ACS

ACS

12 month

post ACS

12 month

post ACS

Revascularization

RevascularizationRevascularizationRevascularization

ACS

Higher risk with

insufficiently controlled

risk factors, suboptimal

lifestyle modifications

and/or medical therapy,

large area at risk of

myocardial ischaemia

Subclinical

phase

Recent diagnosis or

revascularization

(≤ 12 months)

Long-standing diagnosis

Lower risk with

optimally controlled risk

factors, lifestyle changes,

adequate therapy for

secondary prevention

(e.g. aspirin, statins, ACE

inhibitors) and

appropriate

revascularization

Revascularization

12 month

post ACS

ACS

12 month

post ACS

12 month

post ACS

Revascularization

ACS

ESC 2019

Figure 1 Schematic illustration of the natural history of chronic coronary syndromes. ACE = angiotensin-converting enzyme; ACS = acute coronary

syndromes; CCS = chronic coronary syndromes; MI = myocardial infarction.

ESC Guidelines 7

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categorized as either acute coronary syndromes (ACS) or chronic

coronary syndromes (CCS). The Guidelines presented here refer to

the management of patients with CCS. The natural history of CCS is

illustrated in Figure 1 .

The most frequently encountered clinical scenarios in patients

with suspected or established CCS are: (i) patients with suspected

CAD and 'stable' anginal symptoms, and/or dyspnoea (see section 3 );

(ii) patients with new onset of heart failure (HF) or left ventricular

(LV) dysfunction and suspected CAD (see section 4); (iii) asympto-

matic and symptomatic patients with stabilized symptoms <1 year

after an ACS, or patients with recent revascularization (see section

5.1); (iv) asymptomatic and symptomatic patients >1 year after initial

diagnosis or revascularization (see section 5.2); (v) patients with

angina and suspected vasospastic or microvascular disease (see sec-

tion 6); and (vi) asymptomatic subjects in whom CAD is detected at

screening (see section 7 ).

All of these scenarios are classified as a CCS but involve different risks

for future cardiovascular events [e.g. death or myocardial infarction

(MI)], and the risk may change over time. Development of an ACS may

acutely destabilize each of these clinical scenarios. The risk may increase

as a consequence of insufficiently controlled cardiovascular risk factors,

suboptimal lifestyle modifications and/or medical therapy, or unsuccess-

ful revascularization. Alternatively, the risk may decrease as a conse-

quence of appropriate secondary prevention and successful

revascularization. Hence, CCS are defined by the different evolutionary

phases of CAD, excluding situations in which an acute coronary artery

thrombosis dominates the clinical presentation (i.e. ACS).

In the present Guidelines, each section deals with the main clinical

scenarios of CCS. This structure aims to simplify the use of the

Guidelines in clinical practice. Additional information, tables, figures,

and references are available in the Supplementary Data on the ESC

website (www.escardio.org) as well as in The ESC Textbook of

Cardiovascular Medicine.

2.1 What is new in the 2019 Guidelines?

New/revised concepts in 2019

The Guidelines have been revised to focus on CCS instead of stable CAD.

This change emphasizes the fact that the clinical presentations of CAD can be categorized as either ACS or CCS. CAD is a dynamic process of atheroscler-

otic plaque accumulation and functional alterations of coronary circulation that can be modiﬁed by lifestyle, pharmacological therapies, and revascularization,

which result in disease stabilization or regression.

In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identiﬁed: (i) patients with suspected CAD and 'stable' anginal

symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized

symptoms <1 year after an ACS or patients with recent revascularization; (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revasculariza-

tion; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.

The PTP of CAD based on age, gender and nature of symptoms have undergone major revisions. In addition, we introduced a new phrase 'Clinical likelihood of CAD'

that utilizes also various risk factors of CAD as PTP modiﬁers. The application of various diagnostic tests in different patient groups to rule-in or rule-out CAD have been

updated.

The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular

events and mortality.

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.

New major recommendations in 2019

Basic testing, diagnostics, and risk assessment

Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnosing CAD in

symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone. I

It is recommended that selection of the initial non-invasive diagnostic test be based on the clinical likelihood of CAD and other patient

characteristics that inﬂuence test performance, local expertise, and the availability of tests. I

Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional signiﬁcance or is

not diagnostic. I

Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and severe symptoms

refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indicates high event risk. Invasive func-

tional assessment must be available and used to evaluate stenoses before revascularization, unless very high grade (>90% diameter stenosis).

Invasive coronary angiography with the availability of invasive functional evaluation should be considered for conﬁrmation of the diagnosis

of CAD in patients with an uncertain diagnosis on non-invasive testing. IIa

Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or non-diagnostic. IIa

Coronary CTA is not recommended when extensive coronary calciﬁcation, irregular heart rate, signiﬁcant obesity, inability to cooperate

with breath-hold commands, or any other conditions make good image quality unlikely. III

Continued

8ESC Guidelines

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Antithrombotic therapy in patients with CCS and sinus rhythm

Addition of a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with a high

risk of ischaemic events and without high bleeding risk (see options in section 3.3.2 ). IIa

Addition of a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at least a

moderately increased risk of ischaemic events and without high bleeding risk (see options in section 3.3.2 ). IIb

Antithrombotic therapy in patients with CCS and AF

When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in preference to a

VKA. I

Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and a CHA

VASc score >_2 in males and >_3 in females. I

Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF and a

CHA

-VASc score of 1 in males and 2 in females. IIa

Antithrombotic therapy in post-PCI patients with AF or another indication for OAC

In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d., edoxaban 60

mg o.d.,or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy. I

When rivaroxaban is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, rivar-

oxaban 15 mg o.d. should be considered in preference to rivaroxaban 20 mg o.d. for the duration of concomitant single or dual antiplate-

let therapy.

IIa

When dabigatran is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, dabi-

gatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for the duration of concomitant single or dual antipla-

telet therapy

IIa

After uncomplicated PCI, early cessation (<_1 week) of aspirin, and continuation of dual therapy with OAC and clopidogrel, should be

considered if the risk of stent thrombosis is low or if concerns about bleeding risk prevail over concerns about risk of stent thrombosis,

irrespective of the type of stent used.

IIa

Triple therapy with aspirin, clopidogrel, and an OAC for >_1 month should be considered when the risk of stent thrombosis outweighs

the bleeding risk, with the total duration (<_6 months) decided upon according to the assessment of these risks and clearly speciﬁed at

hospital discharge.

IIa

In patients with an indication for a VKA in combination with aspirin and/or clopidogrel, the dose intensity of the VKA should be carefully

regulated with a target international normalized ratio in the range of 2.0 - 2.5 and with time in therapeutic range >70%. IIa

Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with an OAC, aspirin,

and clopidogrel in patients with a moderate or high risk of stent thrombosis, irrespective of the type of stent used. IIb

Other pharmacological therapy

Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC monotherapy

who are at high risk of gastrointestinal bleeding. I

Lipid-lowering drugs: if goals are not achieved with the maximum tolerated dose of statin, combination with ezetimibe is recommended. I

Lipid-lowering drugs: for patients at very high risk who do not achieve their goals on a maximum tolerated dose of statin and ezetimibe,

combination with a PCSK9 inhibitor is recommended. I

ACE inhibitors should be considered in CCS patients at very high risk of cardiovascular adverse events. IIa

The sodium-glucose co-transporter 2 inhibitors empagliﬂozin, canagliﬂozin, or dapagliﬂozin are recommended in patients with diabetes

mellitus and CVD. I

A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes mellitus and CVD. I

Screening for CAD in asymptomatic subjects

Carotid ultrasound IMT for cardiovascular risk assessment is not recommended. III

Recommendations for treatment options for refractory angina

A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refractory to optimal

medical and revascularization strategies. IIb

Class of recommendation.

ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial ﬁbrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic

coronary syndromes; CHA

-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 65 74 and Sex category

[Female]; CTA = computed tomography angiography; CVD = cardiovascular disease; HF = heart failure; IMT = intima-media thickness; LV = left ventricular; NOAC = non-vita-

min K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtili-

sin-kexin type 9; VKA = vitamin K antagonist.

ESC Guidelines 9

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3 Patients with angina and/or

dyspnoea, and suspected coronary

artery disease

3.1 Basic assessment, diagnosis, and risk

assessment

The general approach for the initial diagnostic management of

patients with angina and suspected obstructive CAD is presented

in Figure 2 . The diagnostic management approach includes six

steps. The first step is to assess the symptoms and signs, to

identify patients with possible unstable angina or other forms of

ACS (step 1). In patients without unstable angina or other ACS,

the next step is to evaluate the patient's general condition and

quality of life (step 2). Comorbidities that could potentially influ-

ence therapeutic decisions are assessed and other potential

causes of the symptoms are considered. Step 3 includes basic test-

ing and assessment of LV function. Thereafter, the clinical likeli-

hood of obstructive CAD is estimated (step 4) and, on this basis,

diagnostic testing is offered to selected patients to establish the

diagnosis of CAD (step 5). Once a diagnosis of obstructive CAD

has been confirmed, the patient's event risk will be determined

(step 6) as it has a major impact on the subsequent therapeutic

decisions.

Changes in major recommendations

2013 Class

2019 Class

Exercise ECG is recommendedas the initial test to estab-

lish a diagnosis of stable CAD in patients withsymptoms

of angina and intermediate PTP of CAD (15 65%), free

of anti-ischaemic drugs, unless they cannot exercise or

display ECG changes that make the ECG non-evaluable.

Exercise ECG is recommended for the assessment of exercise tol-

erance, symptoms, arrhythmias, BP response, and event risk in

selected patients.

Exercise ECG may be considered as an alternative test to rule-in

or rule-out CAD when other non-invasive or invasive imaging

methods are not available.

IIb

Exercise ECG should be considered in patients on treat-

ment to evaluate control of symptoms and ischaemia. IIa Exercise ECG may be considered in patients on treatment to evalu-

ate control of symptoms and ischaemia. IIb

For second-line treatment it is recommended that long-

acting nitrates, ivabradine, nicorandil, or ranolazine are

added according to heart rate, BP, and tolerance. IIa

Long-acting nitrates should be considered as a second-line treat-

ment option when initial therapy with a beta-blocker and/or a non-

DHP-CCB is contraindicated, poorly tolerated, or inadequate in

controlling angina symptoms.

IIa

For second-line treatment, trimetazidine may be

considered,

IIb

Nicorandil, ranolazine, ivabradine, or trimetazidine should be con-

sidered as a second-line treatment to reduce angina frequency and

improve exercise tolerance in subjects who cannot tolerate, have

contraindications to, or whose symptoms are not adequately con-

trolled by beta-blockers, CCBs, and long-acting nitrates.

IIa

In selected patients, the combination of a beta-blocker or a CCB

with second-line drugs (ranolazine, nicorandil, ivabradine, and tri-

metazidine) may be considered for ﬁrst-line treatment according

to heart rate, BP, and tolerance.

IIb

In patients with suspected coronary microvascular angina:

intracoronary acetylcholine and adenosine with Doppler

measurements may be considered during coronary arte-

riography, if the arteriogram is visually normal, to assess

endothelium-dependent and non-endothelium-dependent

CFR, and detect microvascular/epicardial vasospasm.

IIb

Guidewire-based CFR and/or microcirculatory resistance measure-

ments should be considered in patients with persistent symptoms,

but coronary arteries that are either angiographically normal or

have moderate stenoses with preserved iwFR/FFR.

IIa

Intracoronary acetylcholine with ECG monitoring may be consid-

ered during angiography, if coronary arteries are either angiograph-

ically normal or have moderate stenoses with preserved iwFR/FFR,

to assess microvascular vasospasm.

IIb

In patients with suspected coronary microvascular angina:

transthoracic Doppler echocardiography of the LAD,

with measurement of diastolic coronary blood ﬂow fol-

lowing intravenous adenosine and at rest, may be consid-

ered for non-invasive measurement of CFR.

IIb

Transthoracic Doppler of the LAD, CMR, and PET may be consid-

ered for non-invasive assessment of CFR.

IIb

Class of recommendation.

BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel blocker; CFR = coronary ﬂow reserve; CMR = cardiac magnetic resonance; DHP-CCB = dihy-

dropyridine calcium channel blockers; ECG = electrocardiogram; FFR = fractional ﬂow reserve; iwFR = instantaneous wave-free ratio (instant ﬂow reserve); LAD = left anterior

descending; PET = positron emission tomography; PTP = pre-test probability.

10 ESC Guidelines

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After these steps, appropriate therapies are to be initiated,

which include lifestyle management (see section 3.2 ), medical

therapy (see section 3.3 ), and revascularization when indicated

(see section 3.4).

3.1.1. Step 1: Symptoms and signs

A careful history is the cornerstone of the diagnosis of angina. It

is possible to achieve a high degree of certainty on a diagnosis

based on history alone, although physical examination and objec-

tive tests are most often necessary to confirm the diagnosis,

exclude alternative diagnoses, and assess the severity of underly-

ing disease. The history should include any manifestation of cardi-

ovascular disease (CVD) and risk factors (i.e. family history of

CVD, dyslipidaemia, diabetes, hypertension, smoking, and other

lifestyle factors).

The characteristics of discomfort related to myocardial ischae-

mia (angina pectoris) may be divided into four categories: location,

character, duration, and relationship to exertion, and other

exacerbating or relieving factors. The discomfort caused by myo-

cardial ischaemia is usually located in the chest, near the sternum,

but may be felt anywhere from the epigastrium to the lower jaw

or teeth, between the shoulder blades, or in either arm to the

wrist and fingers. The discomfort is often described as pressure,

tightness, or heaviness; sometimes strangling, constricting, or

burning. It may be useful to ask the patient directly about the pres-

ence of 'discomfort' as many do not feel 'pain' or 'pressure' in their

chest. Shortness of breath may accompany angina, and chest dis-

comfort may also be accompanied by less-specific symptoms such

as fatigue or faintness, nausea, burning, restlessness, or a sense of

impending doom. Shortness of breath may be the sole symptom of

CAD and it may be difficult to differentiate this from shortness of

breath caused by other conditions.

The duration of the discomfort is brief—<_10 min in the majority

of cases, and more commonly just a few minutes or less—and

chest pain lasting for seconds is unlikely to be due to CAD. An

important characteristic is the relationship to exercise. Symptoms

Assess symptoms and perform clinical investigations

Consider comorbidities and quality of life

Resting ECG, biochemistry, chest X-ray in selected

patients, echocardiography at rest

Assess pre-test probability and clinical likelihood of CAD

STEP 1

STEP 2

STEP 3

STEP 4

Unstable angina?

Revascularization

futile

LVEF <50%

Cause of chest pain

other than CAD?

Follow ACS guidelines

Medical therapy

See section 4

Treat as appropriate or

investigate other causes

Offer diagnostic testing

No diagnostic

testing mandated

Coronary CTA

STEP 5

Clinical likelihood of obstructive CAD Very high

Very low

Choose appropriate therapy based on symptoms and event risk

STEP 6

Invasive

angiography

(with iwFR/FFR)

Testing for ischaemia

(imaging testing preferred)

Choice of the test based on clinical

likelihood, patient characteristics

and preference, availability,

as well as local expertise

©ESC 2019

Figure 2 Approach for the initial diagnostic management of patients with angina and suspected coronary artery disease. ACS = acute coronary

syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = frac-

tional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction.

If the diagnosis of CAD is uncertain, establishing

a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment may be reasonable.

May be omitted in very young and

healthy patients with a high suspicion of an extracardiac cause of chest pain, and in multimorbid patients in whom the echocardiography result has

no consequence for further patient management.

Consider exercise ECG to assess symptoms, arrhythmias, exercise tolerance, BP response, and

event risk in selected patients.

Ability to exercise, individual test-related risks, and likelihood of obtaining diagnostic test result.

High clinical likeli-

hood and symptoms inadequately responding to medical treatment, high event risk based on clinical evaluation (such as ST-segment depression,

combined with symptoms at a low workload or systolic dysfunction indicating CAD), or uncertain diagnosis on non-invasive testing.

Functional

imaging for myocardial ischaemia if coronary CTA has shown CAD of uncertain grade or is non-diagnostic.

Consider also angina without obstruc-

tive disease in the epicardial coronary arteries (see section 6 ).

ESC Guidelines 11

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classically appear or become more severe with increased levels of

exertion—such as walking up an incline or against a breeze, or in

cold weather—and rapidly disappear within a few minutes when

these causal factors abate. Exacerbations of symptoms after a

heavy meal or after waking up in the morning are classic features

of angina. Angina may paradoxically be reduced with further exer-

cise (walk-through angina) or on second exertion (warm-up

angina).

Sublingual nitrates rapidly relieve angina. Symptoms are

unrelated to respiration or position. The angina threshold, and

hence symptoms, may vary considerably from day to day and even

during the same day.

Definitions of typical and atypical angina are summarized in

Table 3 . The classification, although subjective, is practical and of

proven value in determining the likelihood of obstructive CAD.

2, 3

Studies published since 2015 have reported that the majority of

patients suspected of having CAD present with atypical or non-

anginal chest pain,

4 6

with as few as 10 - 15% presenting with typi-

cal angina.

3,7, 8

The Canadian Cardiovascular Society classification

is still widely used as a grading system for angina,

to quantify the

threshold at which symptoms occur in relation to physical activ-

ities (Table 4 ).

Physical examination of a patient with suspected CAD is important

to assess the presence of anaemia, hypertension, valvular heart dis-

ease, hypertrophic cardiomyopathy, or arrhythmias. It is also recom-

mended that practitioners obtain the body mass index (BMI) and

search for evidence of non-coronary vascular disease, which may be

asymptomatic [includes palpation of peripheral pulses, and ausculta-

tion of carotid and femoral arteries, as well as assessment of the

ankle-brachial index (ABI)], and other signs of comorbid conditions

such as thyroid disease, renal disease, or diabetes. This should

be used in the context of other clinical information, such as the pres-

ence of cough or stinging pain, making CAD more unlikely. One

should also try to reproduce the symptoms by palpation

and test

the effect of sublingual nitroglycerin in order to classify the symptoms

(Table 3 ).

3.1.1.1 Stable vs. unstable angina

Unstable angina may present in one of three ways: (i) as rest

angina, i.e. pain of characteristic nature and location occurring at

rest and for prolonged periods (>20 min); (ii) new-onset angina,

i.e. recent (2 months) onset of moderate-to-severe angina

(Canadian Cardiovascular Society grade II or III); or (iii) crescendo

angina, i.e. previous angina, which progressively increases in

severity and intensity, and at a lower threshold, over a short

period of time. Management of angina fulfilling these criteria is

dealt with in the ESC Guidelines for the management of ACS.

11,12

New-onset angina is generally regarded as unstable angina; how-

ever, if angina occurs for the first time with heavy exertion and

subsides at rest, the suspected condition falls under the definition

of CCS rather than unstable angina. In patients with unstable

angina identified as being at low risk, it is recommended that the

diagnostic and prognostic algorithms presented in these

Guidelines be applied once the period of instability has subsided.

Low-risk patients with unstable angina are characterized by no

recurrence of angina, no signs of HF, no abnormalities in the initial

or subsequent electrocardiogram (ECG), and no rise in troponin

levels.

In this setting, a non-invasive diagnostic strategy is recom-

mended before deciding on an invasive strategy. Based on the defi-

nition above, stable and unstable angina may overlap, and many

CCS patients pass through a period of experiencing unstable

angina.

Table 4 Grading of effort angina severity according to the Canadian Cardiovascular Society

Grade Description of angina severity

I Angina only with strenuous exertion Presence of angina during strenuous, rapid, or prolonged ordinary

activity (walking or climbing the stairs).

II Angina with moderate exertion Slight limitation of ordinary activities when they are performed

rapidly, after meals, in cold, in wind, under emotional stress, or

during the ﬁrst few hours after waking up, but also walking uphill,

climbing more than one ﬂight of ordinary stairs at a normal pace,

and in normal conditions.

III Angina with mild exertion Having difﬁculties walking one or two blocks, or climbing one

ﬂight of stairs, at normal pace and conditions.

IV Angina at rest No exertion needed to trigger angina.

Table 3 Traditional clinical classiﬁcation of suspected

anginal symptoms

Typical angina Meets the following three characteristics:

(i) Constricting discomfort in the front of the chest or

in the neck, jaw, shoulder, or arm;

(ii) Precipitated by physical exertion;

(iii) Relieved by rest or nitrates within 5 min.

Atypical angina Meets two of these characteristics.

Non-anginal

chest pain

Meets only one or none of these characteristics.

12 ESC Guidelines

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3.1.1.2 Distinction between symptoms caused by epicardial vs. microvas-

cular/vasospastic disease

A distinction between symptoms caused by an epicardial stenosis and

symptoms caused by microvascular or vasospastic disease cannot be

made with reasonable certainty. Reliance on ischaemia testing or

depiction of the coronary anatomy is often unavoidable to exclude

obstructive CAD, which can be absent in symptomatic patients.

13,14

A diagnostic workup for microvascular or vasospastic disease is dis-

cussed in section 6 of these Guidelines.

3.1.2 Step 2: Comorbidities and other causes of

symptoms

Before any testing is considered, one must assess the patient's general

health, comorbidities, and quality of life. If revascularization is unlikely

to be an acceptable option, further testing may be reduced to a clini-

cally indicated minimum and appropriate therapy should be insti-

tuted, which may include a trial of antianginal medication even if a

diagnosis of CAD has not been fully demonstrated. Non-invasive

functional imaging for ischaemia may be an option if there is need to

verify the diagnosis (Figure 2 ).

If the pain is clearly non-anginal, other diagnostic testing may be

indicated to identify gastrointestinal, pulmonary, or musculoskeletal

causes of chest pain. Nevertheless, these patients should also

receive Guideline-based risk-factor modification based on commonly

applied risk charts such as SCORE (Systematic COronary Risk

Evaluation) (www.heartscore.org).

3.1.3 Step 3: Basic testing

Basic (first-line) testing in patients with suspected CAD includes stand-

ard laboratory biochemical testing, a resting ECG, possible ambulatory

ECG monitoring, resting echocardiography, and, in selected patients, a

chestX-ray.Suchtestingcanbedoneonanoutpatientbasis.

3.1.3.1 Biochemical tests

Laboratory investigations are used to identify possible causes of

ischaemia, to establish cardiovascular risk factors and associated

conditions, and to determine prognosis. Haemoglobin as part of a

full blood count and—where there is a clinical suspicion of a thy-

roid disorder—thyroid hormone levels provide information

related to possible causes of ischaemia. Fasting plasma glucose and

glycated haemoglobin (HbA1c) should be measured in every

patient with suspected CAD. If both are inconclusive, an additional

oral glucose tolerance test is recommended.

Knowledge of glu-

cose metabolism is important because of the well-recognized asso-

ciation between diabetes and adverse cardiovascular outcome.

Patients with diabetes should be managed according to specific

Guidelines.

15,16

A lipid profile, including total cholesterol, high-

density lipoprotein cholesterol, low-density lipoprotein cholesterol

(LDL-C), and triglycerides, should also be evaluated in any patient

with suspected CAD to establish the patient's risk profile and

ascertain the need for treatment.

15,17

To characterize severe dysli-

pidaemia or follow-up on high triglyceridaemia, fasting values are

recommended.

Peripheral artery disease (PAD) and renal dysfunction increase the

likelihood of CAD, and have a negative impact on prognosis.

1820

Hence, baseline renal function should be evaluated with estimation of

the glomerular filtration rate (GFR). It may also be reasonable to

measure the uric acid level, as hyperuricaemia is a frequent comorbid

condition and may also 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 should follow the Guidelines for ACS without persis-

tent ST-segment elevation.

If high-sensitivity assays are employed,

low levels of troponin can be detected in many patients with stable

angina. Increased troponin levels are associated with adverse out-

come

2125

and small studies have indicated a possible incremental

value in diagnosing CAD,

26,27

but larger trials are needed to verify

the utility of systematic assessment in patients suspected of CAD.

While multiple biomarkers may be useful for prognostication

(see section 5 ), they do not yet have a role in diagnosing obstructive

CAD.

Basic biochemistry testing in the initial diagnostic management of patients with suspected coronary artery disease

Recommendations Class

Level

If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or

ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.

28,29

The following blood tests are recommended in all patients:

•Full blood count (including haemoglobin);

•Creatinine measurement and estimation of renal function;

31,32

•A lipid proﬁle (including LDL-C).

33,34

It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-

mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c

and fasting plasma glucose results are inconclusive.

16,35

Assessment of thyroid function is recommended in case of clinical suspicion of thyroid disorders. IC

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein

cholesterol.

Class of recommendation.

Level of evidence.

ESC Guidelines 13

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3.1.3.2 Resting electrocardiogram and ambulatory monitoring

The paradigm of diagnosing myocardial ischaemia has, for almost a

century, been based on the detection of repolarization abnormalities,

mainly in the form of ST-segment depressions. Thus, the resting 12

lead ECG remains an indispensable component of the initial evalua-

tion of a patient with chest pain without an obviously non-cardiac

cause. Two scenarios of clinical evaluation are encountered: (i) a

patient without symptoms of chest pain or discomfort, and (ii) a

patient with ongoing anginal symptoms.

The former situation is far more prevalent and a normal resting

ECG is frequently recorded. However, even in the absence of repola-

rization abnormalities, an ECG can demonstrate indirect signs of

CAD, such as signs of previous MI (pathological Q waves) or conduc-

tion abnormalities [mainly left bundle branch block (LBBB) and

impairment of atrioventricular conduction]. Atrial fibrillation (AF) is a

frequent finding in patients with chest pain (usually atypical). ST-

segment depression during supraventricular tachyarrhythmias is not

predictive of obstructive CAD.

3639

The ECG can be crucial for diagnosing myocardial ischaemia if

dynamic ST-segment changes are recorded during ongoing angina.

The diagnosis of Prinzmetal and vasospastic angina is based on the

detection of typical transient ST-segment elevation or depression

during an angina attack (usually at rest).

Long-term ambulatory ECG monitoring and recording should not

be used to replace exercise testing; however, 12 lead ECG monitor-

ing can be considered in selected patients to detect anginal episodes

unrelated to physical exercise. Ambulatory ECG monitoring may

reveal evidence of silent myocardial ischaemia in patients with

CCS, but rarely adds relevant diagnostic or prognostic information

that cannot be derived from stress testing.

ECG changes suggesting

ischaemia on ambulatory ECG monitoring are very frequent in

women, but do not correlate with findings during stress testing.

Most importantly, therapeutic strategies targeting silent ischaemia

detected by ambulatory monitoring have not demonstrated clear

survival benefits.

42, 43

3.1.3.3 Echocardiography and magnetic resonance imaging at rest

An echocardiographic study will provide important information about

cardiac function and anatomy. LV ejection fraction (LVEF) is often nor-

malinpatientswithCCS.

A decreased LV function and/or regional

wall motion abnormalities may increase the suspicion of ischaemic

myocardial damage,

and a pattern of LV dysfunction following the

theoretical distribution territory of the coronary arteries is typical in

patients who have already had an MI.

46,47

The detection of regional

wall motion abnormalities can challenging by visual assessment, and

detection of early systolic lengthening, decreased systolic shortening,

or post-systolic shortening by strain imaging techniques might be help-

fulinpatientswithapparentlynormalLVfunctionbutwithclinicalsus-

picion of CCS.

4850

Decreased diastolic LV function has been

reported to be an early sign of ischaemic myocardial dysfunction and

could also be indicative of microvascular dysfunction.

51, 52

Echocardiography is an important clinical tool for the exclusion of

alternative causes ofchest pain and also aids in diagnosing concurrent

cardiac diseases, such as valvular heart diseases, HF, and most cardio-

myopathies,

but it is important to remember that these diseases

often coexist with obstructive CAD. The use of an echocardio-

graphic contrast agent can be useful in patients with poor acoustic

windows.

Cardiac magnetic resonance (CMR) may be considered in

patients with suspected CAD when the echocardiogram (having

used contrast) is inconclusive.

CMR will provide useful informa-

tion on cardiac anatomy and systolic cardiac function, similar to

that from an echocardiogram, in patients with no contraindications

for CMR. CMR can assess global and regional function,

and the

use of late gadolinium enhancement CMR can reveal a typical pat-

tern of scarred myocardium in patients who have already experi-

enced an MI.

Assessment of LV function is important in all patients for risk strati-

fication (see Supplementary Data section 3.2) and should therefore be

performed in all symptomatic patients with suspected CAD.

Resting electrocardiogram in the initial diagnostic man-

agement of patients with suspected coronary artery

disease

Recommendations Class

Level

A resting 12 lead ECG is recommended in all

patients with chest pain without an obvious

non-cardiac cause.

A resting 12 lead ECG is recommended in all

patients during or immediately after

an episode of angina suspected to be indicative

of clinical instability of CAD.

ST-segment alterations recorded during

supraventricular tachyarrhythmias should not

be used as evidence of CAD.

III C

CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =

electrocardiogram.

Class of recommendation.

Level of evidence.

Ambulatory electrocardiogram monitoring in the initial

diagnostic management of patients with suspected coro-

nary artery disease

Recommendations Class

Level

Ambulatory ECG monitoring is recommended

in patients with chest pain and

suspected arrhythmias.

Ambulatory ECG recording, preferably moni-

toring with 12 lead ECG, should be consid-

ered in patients with suspected vasospastic

angina.

IIa C

Ambulatory ECG monitoring should not be

used as a routine examination in patients with

suspected CCS.

III C

CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =

electrocardiogram.

Class of recommendation.

Level of evidence.

14 ESC Guidelines

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Management of patients with either angina or HF symptoms, with

reduced LVEF <40% or a mid-range reduced LVEF of 40-49%, is

described in section 4 of the Guidelines.

3.1.3.4 Chest X-ray

Chest X-ray is frequently used in the assessment of patients with

chest pain. However, in CCS, it does not provide specific information

for diagnosis or event risk stratification. The test may occasionally be

helpful in assessing patients with suspected HF. Chest X-ray may also

be useful in patients with pulmonary problems, which often accom-

pany CAD, or to rule-out another cause of chest pain in atypical

presentations.

3.1.4 Step 4: Assessment of pre-test probability and clini-

cal likelihood of coronary artery disease

The performance of the available methods in diagnosing obstructive

CAD (i.e. the likelihood that the patient has disease if the test is

abnormal, and the likelihood that the patient does not have disease if

the test is normal) depends on the prevalence of disease in the

population studied and, thus, the likelihood that a given patient will

actually have CAD. Diagnostic testing is most useful when the likeli-

hood is intermediate. When likelihood is high, a large number of

patients need to be studied to identify the few patients that do not

have disease, and a negative test result can seldom rule out the pres-

ence of obstructive CAD (i.e. the negative predictive value is low).

When the likelihood is low, a negative test can rule out the disease,

but the lower the likelihood, the higher the likelihood of a false-

positive test (i.e. a positive test in the absence of obstructive CAD).

In patients at the extreme ends of the probabilityrange, it is therefore

reasonable to refrain from diagnostic testing, and assume that the

patient does or does not have obstructive CAD based on clinical

evaluation alone.

The likelihood of obstructive CAD is influenced by the prevalence

of the disease in the population studied, as well as by clinical features

of an individual patient. A simple predictive model canbe usedto esti-

mate the pre-test probability (PTP) of obstructive CAD based on

age, sex, and the nature of symptoms.

In the previous version of

these Guidelines,

estimation of the PTP was based on data gathered

by Genders et al.,

which updated previous data from Diamond and

Forrester.

Notably, the prevalence of disease for a given constella-

tion of age, sex, and nature of symptoms was lower than in

the Diamond and Forrester data. Since the previous version of the

Guidelines was published, several studies have indicated that

the prevalence of obstructive disease among patients with suspected

CAD is lower than in theprevious update.

7,8,62,63

A pooled analysis

of three contemporary study cohorts, includ-

ing patients evaluated for suspected CAD,

7,8,62

has indicated that the

PTP based on age, sex, and symptoms is approximately one-third of

that predicted by the model used in the previous version of the

Guidelines.

57,62

Overestimation of PTP is an important contributory

factor to a low diagnostic yield of non-invasive and invasive testing.

The new set of PTPs presented in Table 5 may substantially reduce

the need for non-invasive and invasive tests in patients with suspected

stable CAD. The table now also includes patients presenting with

dyspnoea as their main symptom. However, it should be noted that

the PTPs presented in Table 5 (as well as the PTP table in the previous

version of the Guidelines) are based mainly on patients from coun-

tries with low CVD risk, and may vary between regions and

countries.

Application of the new PTPs (Table 5 ) has important conse-

quences for the referral of patients for diagnostic testing. If diag-

nostic testing was deferred in patients with a new PTP <15%, this

would result in a large increase in the proportion of patients for

whom diagnostic testing was not recommended, because more

patients are classified as having a PTP <15%. In data derived from

the PROMISE (Prospective Multicenter Imaging Study for

Evaluation of Chest Pain) trial, 50% of patients previously classified

as having an intermediate likelihood of obstructive CAD were

reclassified to a PTP <15% according to the new PTP.

In data

derived from the pooled analysis

(Table 5 ), 57% of all patients

were classified to a PTP <15%.

Studies have shown that outcomes in patients classified with

the new PTP <15% is good (annual risk of cardiovascular death

or MI is <1%).

7, 62

Hence, it is safe to defer routine testing in

patients with PTP <15%, thus reducing unnecessary procedures

and costs.

Resting echocardiography and cardiac magnetic reso-

nance in the initial diagnostic management of patients

with suspected coronary artery disease

Recommendations Class

Level

A resting transthoracic echocardiogram is rec-

ommended in all patients for:

(1) Exclusion of alternative causes of angina;

(2) Identiﬁcation of regional wall motion

abnormalities suggestive of CAD;

(3) Measurement of LVEF for risk stratiﬁca-

tion; and

(4) Evaluation of diastolic function.

44,45,52,58

Ultrasound of the carotid arteries should be

considered, and be performed by adequately

trained clinicians, to detect plaque in patients

with suspected CCS without known athero-

sclerotic disease.

IIa C

CMR may be considered in patients with an

inconclusive echocardiographic test. IIb C

CAD = coronary artery disease; CCS = chronic coronary syndromes; CMR =

cardiac magnetic resonance imaging; LVEF = left ventricular ejection fraction.

Class of recommendation.

Level of evidence.

Chest X-ray in the initial diagnostic management of

patients with suspected coronary artery disease

Recommendation Class

Level

Chest X-ray is recommended for patients

with atypical presentation, signs and symptoms

of HF, or suspicion of pulmonary disease.

HF = heart failure.

Class of recommendation.

Level of evidence.

ESC Guidelines 15

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Recent studies have also demonstrated that, when tested, the

true observed prevalence of obstructive CAD has been <5% in

patients who had a PTP <15% according to the 2013 version of

these Guidelines.

7,63

Therefore, this Task Force recognizes that

the performance of diagnostic testing in patients with a new PTP

of 5 - 1 5% more c losely reflects curren t clinical practice and may

be considered, particularly if symptoms are limiting and require

clarification.

7,63

Patient preference, local resources and the avail-

ability of tests, clinical judgement, and appropriate patient informa-

tion remain important when making a decision to proceed with

non-invasive diagnostic testing for an individual patient when the

PTP is 5 - 15%, and the higher likelihood of a f alse-positive tes t

must be considered. Patients with a PTP <_5% can be assumed to

have such a low probability of disease that diagnostic testing

should be performed only for compelling reasons. Implementation

of the new PTPs also indicates that patients should not be rou-

tinely referred directly to invasive assessment unless clinical or

other data indicate a high likelihood of obstructive CAD.

Clinical models that incorporate information on risk factors for

CVD, resting ECG changes, or coronary calcification have improved

the identification of patients with obstructive CAD compared with

age, sex, and symptoms alone.

3,7, 60 ,6568

Therefore, the presence of

risk factors for CVD (such as family history of CVD, dyslipidaemia,

diabetes, hypertension, smoking, and other lifestyle factors) that

increase the probability of obstructive CAD can be used as modifiers

of the PTP estimate. If available, Q-wave, ST-segment, or T-wave

changes on the ECG, LV dysfunction suggestive of ischaemia, and

findings on exercise ECG, as well as information on coronary calcium

obtained by computed tomography (CT), can be used to improve

estimations of the PTP of obstructive CAD.

3,69

In particular, the

absence of coronary calcium (Agatston score = 0) is associated with

a low prevalence of obstructive CAD (<5%), and low risk of death or

non-fatal MI (<1% annual risk).

69,70

However, it should be noted that

coronary calcium imaging does not exclude coronary stenosis caused

by a non-calcified atherosclerotic lesion,

and the presence of coro-

nary calcium is a weak predictor of obstructive CAD.

Although the

optimal use of these factors in improving PTP assessment has not yet

been established, they should be considered in addition to the PTP

based on sex, age, and the nature of symptoms to determine the

overall clinical likelihood of obstructive CAD, as summarized in

Figure 3. This is particularly important in refining the likelihood of

CAD patients with a PTP of 5 15% based on age, sex, and the nature

of symptoms.

3.1.5 Step 5: Selecting appropriate testing

In patients in whom revascularization is futile due to comorbidities

and overall quality of life, the diagnosis of CAD can be made clini-

cally and only medical therapy is required. If the diagnosis of CAD

is uncertain, establishing a diagnosis using non-invasive functional

imaging for myocardial ischaemia before treatment is reasonable

(Figure 2 ).

In a patient with a high clinical likelihood of CAD, symptoms unre-

sponsive to medical therapy or typical angina at a low level of exer-

cise, and an initial clinical evaluation (including echocardiogram and,

in selected patients, exercise ECG) that indicates a high event risk,

proceeding directly to invasive coronary angiography (ICA) without

further diagnostic testing is a reasonable option. Under such circum-

stances, the indication for revascularization should be based on

appropriate invasive confirmation of the haemodynamic significance

of a stenosis.

71, 72

In other patients in whom CAD cannot be excluded by

clinical assessment alone, non-invasive diagnostic tests are recom-

mended to establish the diagnosis and assess the event risk.

The current Guidelines recommend the use of either non-

invasive functional imaging of ischaemia or anatomical imaging using

coronary CT angiography (CTA) as the initial test for diagnosing CAD.

3.1.5.1 Functional non-invasive tests

Functional non-invasive tests for the diagnosis of obstructive CAD

are designed to detect myocardial ischaemia through ECG

changes, wall motion abnormalities by stress CMR or stress echo-

cardiography, or perfusion changes by single-photon emission CT

Table 5 Pre-test probabilities of obstructive coronary artery disease in 15 815 symptomatic patients according to age,

sex, and the nature of symptoms in a pooled analysis

of contemporary data

7,8,62

Typical Atypical Non-anginal

Age Men Women Men Women Men Women

30–39 3% 5% 4% 3% 1% 1%

40–49 22% 10% 10% 6% 3% 2%

50–59 32% 13% 17% 6% 11% 3%

60–69 44% 16% 26% 11% 22% 6%

70+ 52% 27% 34% 19% 24% 10%

Dyspnoeaa

Men Women

0% 3%

12% 3%

20% 9%

27% 14%

32% 12%

©ESC 2019

CAD = coronary artery disease; PTP = pre-test probability.

In addition to the classic Diamond and Forrester classes,

patients with dyspnoea only or dyspnoea as the primary symptom are included. The regions shaded dark green

denote the groups in which non-invasive testing is most beneﬁcial (PTP >15%). The regions shaded light green denote the groups with PTPs of CAD between 5 15%, in which

testing for diagnosis may be considered after assessing the overall clinical likelihood based on the modiﬁers of PTPs presented in Figure 3.

16 ESC Guidelines

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(SPECT), positron emission tomography (PET), myocardial con-

trast echocardiography, or contrast CMR. Ischaemia can be pro-

voked by exercise or pharmacological stressors, either by

increased myocardial work and oxygen demand, or by heteroge-

neity in myocardial perfusion by vasodilatation. Non-invasive func-

tional tests are associated with high accuracy for the detection of

flow-limiting coronary stenosis compared with invasive functional

testing [fractional flow reserve (FFR)].

However, lower-grade

coronary atherosclerosis not linked with ischaemia remains unde-

tected by functional testing and, in the presence of a negative func-

tional test, patients should receive risk-factor modification based

on commonly applied risk charts and recommendations.

3.1.5.2 Anatomical non-invasive evaluation

Anatomical non-invasive evaluation, by visualizing the coronary artery

lumen and wall using an intravenous contrast agent, can be performed

with coronary CTA, which provides high accuracy for the detection

of obstructive coronary stenoses defined by ICA,

because both tests

are based on anatomy. However, stenoses estimated to be 50 90%

by visual inspection are not necessarily functionally significant, i.e. they

do not always induce myocardial ischaemia.

73,74

Therefore, either

non-invasive or invasive functional testing is recommended for further

evaluation of angiographic stenosis detected by coronary CTA or

invasive angiography, unless a very high-grade (>90% diameter steno-

sis) stenosis is detected via invasive angiography. The presence or

absence of non-obstructive coronary atherosclerosis on coronary

CTA provides prognostic information, and can be used to guide pre-

ventive therapy.

The SCOT-HEART (Scottish Computed

Tomography of the HEART) trial demonstrated a significantly lower

rate of the combined endpoint of cardiovascular death or non-fatal MI

(2.3 vs. 3.9% during 5 year follow-up) in patients in whom coronary

CTA was performed in addition to routine testing, which consisted

predominantly of exercise ECG.

Other randomized, prospective clin-

ical trials have demonstrated that diagnostic testing with coronary

CTA is associated with clinical outcomes similar to those for func-

tional imaging in patients with suspected CAD.

4,6, 76

In patients with

extensive CAD, coronary CTA complemented by CT-based FFR was

non-inferior to ICA and FFR for decision-making, and the identification

of targets for revascularization.

3.1.5.3 Role of the exercise electrocardiogram

Exercise ECG has inferior diagnostic performance compared with

diagnostic imaging tests, and has limited power to rule-in or rule-out

obstructive CAD.

Since the publication of the previous version of

these Guidelines, randomized clinical trials (RCTs) have compared

the effects of diagnostic strategies based on exercise ECG or animag-

ing diagnostic test

6,78,79

on clinical outcomes. These studies have

shown that the addition of coronary CTA

5,6,78, 80

or functional

imaging

clarifies the diagnosis, enables the targeting of preventive

therapies and interventions, and potentially reduces the risk of MI

compared with an exercise ECG. Some, although not all, registry

studies have also shown similar benefits regarding the use of an imag-

ing diagnostic test in patients treated in everyday clinical practice.

81,82

Therefore, these Guidelines recommend the use of an imaging diag-

nostic test instead of exercise ECG as the initial test for to diagnose

obstructive CAD.

An exercise ECG alone may be considered as an alternative to

diagnose obstructive CAD if imaging tests are not available, keeping

in mind the risk of false-negative and false-positive test results.

73,83

An exercise ECG is of no diagnostic value in patients with ECG

abnormalities that prevent interpretation of the ST-segment changes

during stress (i.e. LBBB, paced rhythm, Wolff-Parkinson-White syn-

drome, >_0.1 mV ST-segment depression on resting ECG, or who are

being treated with digitalis). An exercise ECG provides

ESC 2019

PTP based on sex, age and nature of symptoms (Table 5)

Clinical likelihood of CAD

Decreases likelihood

• Normal exercise ECG

• No coronary calcium by CT

(Agatston score = 0)

Increases likelihood

• Risk factors for CVD

(dyslipidaemia, diabetes,

hypertension, smoking,

family history of CVD)

• Resting ECG changes

(Q-wave or ST-segment/

T-wave changes)

• LV dysfunction suggestive

of CAD

• Abnormal exercise ECG

• Coronary calcium by CT

Figure 3 Determinants of the clinical likelihood of obstructive coronary artery disease. CAD = coronary artery disease; CT = computed tomography,

CVD = cardiovascular disease,ECG = electrocardiogram, LV = left ventricular;PTP = pre-test probability.

When available.

ESC Guidelines 17

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complementary clinically useful information beyond ECG changes

and valuable prognostic information. Therefore, application of an

exercise ECG may be considered in selected patients to complement

clinical evaluation for the assessment of symptoms, ST-segment

changes, exercise tolerance, arrhythmias, blood pressure (BP)

response, and event risk.

3.1.5.4 Selection of diagnostic tests

Either a functional or anatomical test can be used to establish a diag-

nosis of obstructive CAD. A summary of the main diagnostic path-

ways is displayed in Figure 4 . For revascularization decisions,

information on both anatomy and ischaemia is needed.

3.1.5.5 The impact of clinical likelihood on the selection of a diagnostic test

Each non-invasive diagnostic test has a particular range of clinical like-

lihood of obstructive CAD where the usefulness of its application is

maximal. The likelihood ratios of the tests constitute useful parame-

ters of their abilities to correctly classify patients, and can be used to

facilitate the selection of the most useful test in any given patient.

73,84

Given a clinical likelihood of obstructive CAD and the likelihood ratio

of a particular test, one can assess the post-test probability of

obstructive CAD after performing such a test. Using this approach,

one can estimate the optimal ranges of clinical likelihood for each

test, where they can reclassify patients from intermediate to either

low or high post-test probability of CAD (Figure 5 ).

Coronary CTA is the preferred test in patients with a lower range

of clinical likelihood of CAD, no previous diagnosis of CAD, and

characteristics associated with a high likelihood of good image quality.

It detects subclinical coronary atherosclerosis, but can also accu-

rately rule out both anatomically and functionally significant CAD

(Figure 5 ). It has higher accuracy values when low clinical likelihood

populations are subjected to examination.

Trials evaluating out-

comes after coronary CTA to date have mostly included patients

with a low clinical likelihood.

4,5

The non-invasive functional tests for ischaemia typically have bet-

ter rule-in power. In outcome trials, functional imaging tests have

been associated with fewer referrals for downstream ICA compared

with a strategy relying on anatomical imaging.

55,76,86

Before revascula-

rization decisions can be made, functional evaluation of ischaemia

(either non-invasive or invasive) is required in most patients.

Therefore, functional non-invasive testing may be preferred in

patients at the higher end of the range of clinical likelihood if revascu-

larization is likely or the patient has previously diagnosed CAD.

Patients in whom CAD is suspected, but who have a very low clini-

cal likelihood (<_5%) of CAD, should have other cardiac causes of

chest pain excluded and their cardiovascular risk factors adjusted,

based on a risk-score assessment. In patients with repeated, unpro-

voked attacks of anginal symptoms mainly at rest, vasospastic angina

should be considered, diagnosed, and treated appropriately

(see section 6).

ESC 2019

Non-invasive

testing for

ischaemia

Preferentially considered if:

 High clinical likelihood

 Revascularization likely

 Local expertise and availability

 Viability assessment also required

Preferentially considered if:

 High clinical likelihood and severe

symptoms refractory to medical therapy

 Typical angina at low level of exercise and

clinical evaluation including exercise ECG

indicates high-risk of events

 LV dysfunction suggestive of CAD

Preferentially considered if:

 Low clinical likelihood

 Patient characteristics suggest

high image quality

 Local expertise and availability

 Information on atherosclerosis

desired

 No history of CAD

Invasive

coronary

angiography

Revascularization

Coronary

CTA

Drug

therapyb

Functional

assessment

Drug

therapyb

Ongoing

symptomsa

Stenosis >90%

or with established

correlation to ischaemia

Figure 4 Main diagnostic pathways in symptomatic patients with suspected obstructive coronary artery disease. Depending on clinical conditions and

the healthcare environment, patient workup can start with either of three options: non-invasive testing, coronary computed tomography angiography, or

invasive coronary angiography. Through each pathway, both functional and anatomical information is gathered to inform an appropriate diagnostic and

therapeutic strategy. Risk-factor modification should be considered in all patients. CAD = coronary artery disease; CTA = computed tomography angiog-

raphy; ECG = electrocardiogram; LV = left ventricular.

Consider microvascular angina.

Antianginal medications and/or risk-factor modification.

18 ESC Guidelines

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In addition to diagnostic accuracy and clinical likelihood, the selec-

tion of a non-invasive test depends on other patient characteristics,

local expertise, and the availability of tests. Some diagnostic tests may

perform better in some patients than others. For example, irregular

heart rate and the presence of extensive coronary calcification are

associated with increased likelihood of non-diagnostic image quality

of coronary CTA, and it is not recommended in such patients.

Stress echocardiography or SPECT perfusion imaging can be com-

bined with dynamic exercise testing, and may be preferred if addi-

tional information available from the exercise test, such as exercise

tolerance or heart rate response to exercise, is considered impor-

tant. Exercise ECG cannot be used for diagnostic purposes in the

presence of ECG abnormalities that prevent the evaluation of ischae-

mia. Risks related to different diagnostic tests need to be weighed

against the benefits to the individual.

For example, exposure to ion-

izing radiation associated with coronary CTA and nuclear perfusion

imaging needs to be taken into account, especially in young individu-

als.

Similarly, contraindications to pharmacological stressors and

contrast agents (iodine-based contrast agents and gadolinium-based

chelates) need to be taken into account. When testing is used appro-

priately, the clinical benefit from accurate diagnosis and therapy

exceeds the projected risks of testing itself.

3.1.5.6 Invasive testing

For diagnostic purposes, ICA is only necessary in patients with sus-

pected CAD in cases of inconclusive non-invasive testing or, exception-

ally, in patients from particular professions, due to regulatory issues.

However, ICA may be indicated if non-invasive assessment suggests

high event risk for determination of options for revascularization.

In a patient with a high clinical likelihood of CAD, and symptoms

unresponsive to medical therapy or with typical angina at a low level

of exercise, and initial clinical evaluation indicates a high event risk,

early ICA without previous non-invasive risk stratification may be

reasonable to identify lesions potentially amenable to revasculariza-

tion (Figure 4 ). Invasive functional assessment should complement

ICA, especially in patients with coronary stenoses of 50 - 90% or mul-

tivessel disease, given the frequent mismatch between the angio-

graphic and haemodynamic severities of coronary stenoses.

8991

Systematic integration of ICA with FFR has been shown to result in

changes to the management strategies of 30 - 50% of patients under-

going elective ICA.

92,93

Methods used to perform ICA have improved

substantially, resulting in a reduction of complication rates with rapid

ambulation. This is especially true for ICA performed via the radial

artery.

The composite rate of major complications associated with

routine femoral diagnostic catheterization—mainly bleeding requir-

ing blood transfusions—is still 0.5 2%.

The composite rate of

death, MI, or stroke is of the order of 0.1 0.2%.

ICA should not be

performed in patients with angina who refuse invasive procedures,

prefer to avoid revascularization, who are not candidates for percuta-

neous coronary intervention (PCI) or coronary artery bypass grafting

(CABG), or in whom revascularization is not expected to improve

functional status or quality of life. Intracoronary techniques for the

diagnostic assessment of coronary anatomy are briefly mentioned in

the Supplementary Data of this document.

ESC 2019

Test

Results

Stress ECG

Coronary CTA

Stress

CMR

SPECT

Stress

Echocardiography

PET

Test

Results

ICA

Coronary CTA

Stress

CMR

SPECT

Clinical Likelihood range where test

can rule-in CAD (Post-test probability will rise above 85%)

Clinical Likelihood range where test

can rule-out CAD (Post-test probability will rise below 15%)

PET

Clinical Likelihood of ICA-significant CAD

15% 85%

100%50%

Clinical Likelihood of FFR -significant CAD

15% 85%

100%50%

Figure 5 Ranges of clinical likelihood of coronary artery disease in which a given test can rule-in (red) or rule-out (green) obstructive coronary

artery disease. (A ) Reference standard is anatomical assessment using invasive coronary angiography. (B ) Reference standard is functional assess-

ment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are

more limited than with the other techniques.

The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from

Knuuti et al .

CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocar-

diogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emis-

sion computed tomography.

ESC Guidelines 19

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Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected coronary

artery disease

Recommendations Class

Level

Non-invasive functional imaging for myocardial ischaemia

or coronary CTA is recommended as the initial test to diagnose

CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.

4,5, 55,73,7880

It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD

and other patient characteristics that inﬂuence test performance,

local expertise, and the availability of tests. IC

Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-

niﬁcance or is not diagnostic.

4, 55,73

Invasive coronary angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likeli-

hood, severe symptoms refractory to medical therapy or typical angina at a low level of exercise, and clinical evaluation

that indicates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revas-

cularization, unless very high grade (>90% diameter stenosis).

71,72,74

Invasive coronary angiography with the availability of invasive functional evaluation should be considered for conﬁrmation

of the diagnosis of CAD in patients with an uncertain diagnosis on non-invasive testing.

71,72

IIa B

Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or

non-diagnostic. IIa C

Coronary CTA is not recommended when extensive coronary calciﬁcation, irregular heart rate, signiﬁcant obesity, inabil-

ity to cooperate with breath-hold commands, or any other conditions make obtaining good image quality unlikely. III C

Coronary calcium detection by CT is not recommended to identify individuals with obstructive CAD. III C

CAD = coronary artery disease; CT = computed tomography; CTA = computed tomography angiography.

Class of recommendation.

Level of evidence

Stress echocardiography, stress cardiac magnetic resonance, single-photon emission CT, or positron emission tomography.

Characteristics determining ability to exercise, likelihood of good image quality, expected radiation exposure, and risks or contraindications.

Use of exercise electrocardiogram in the initial diagnostic management of patients with suspected coronary artery

disease

Recommendations Class

Level

Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event

risk in selected patients.

Exercise ECG may be considered as an alternative test to rule-in and rule-out CAD when non-invasive imaging is not

available.

73,83

IIb B

Exercise ECG may be considered in patients on treatment to evaluate control of symptoms and ischaemia. IIb C

Exercise ECG is not recommended for diagnostic purposes in patients with >_0.1 mV ST-segment depression on resting

ECG or who are being treated with digitalis. III C

BP = blood pressure; CAD = coronary artery disease; ECG = electrocardiogram.

Class of recommendation.

Level of evidence.

When this information will have an impact on diagnostic strategy or management.

20 ESC Guidelines

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3.1.6 Step 6: Assessment of event risk

Assessment of event risk is recommended in every patient being eval-

uated for suspected CAD or with a newly diagnosed CAD, as it has

major impacts on therapy decisions. The process of risk stratification

serves to identify patients at high event risk who will benefit from

revascularization beyond the amelioration of symptoms. Event risk

stratification is usually based on the assessments used to make a diag-

nosis of CAD. All patients should undergo cardiovascular event risk

stratification using clinical evaluation, the assessment of LV function by

resting echocardiography, and, in the majority of cases, non-invasive

assessment of ischaemia or coronary anatomy. Although the diagnos-

tic value of an exercise ECG is limited,

theoccurrenceofST-

segment depression at a low workload combined with exertional

symptoms (angina or dyspnoea), low exercise capacity, complex ven-

tricular ectopy, or arrhythmias and abnormal BP response are

markers of a high risk of cardiac mortality.

97100

Patients with typical

Table 6 Deﬁnitions of high event risk for different test modalities in patients with established chronic coronary syndro-

mes

a102104

Exercise ECG Cardiovascular mortality >3% per year according to Duke Treadmill Score

SPECT or PET perfusion imaging Area of ischaemia >_10% of the left ventricle myocardium

Stress echocardiography >_3 of 16 segments with stress-induced hypokinesia or akinesia

CMR >_2 of 16 segments with stress perfusion defects or >_3 dobutamine-induced dysfunctional segments

Coronary CTA or ICA Three-vessel disease with proximal stenoses, LM disease, or proximal anterior descending disease

Invasive functional testing FFR <_0.8, iwFR <_0.89

CTA = computed tomography angiography; CMR = cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional ﬂow reserve; ICA = invasive coronary angiography;

iwFR = instantaneous wave-free ration (instant ﬂow reserve); LM = left main; PET = positron emission tomography; SPECT; single-photon emission computed tomography.

For detailed explanations, refer to the Supplementary Data.

ESC 2019

15% and over

10%

–

14%

–

<1%

Very high-risk

High-risk

Low-to-moderate risk

Symptomatic patients with established CCSAsymptomatic apparently healthy subjects

Annual risk of cardiac mortality10 year risk of cardiovascular mortality

3% and over

1%–2.9%

0%–0.9%

High-risk

Moderate risk

Low-risk

0,5

1,5

2,5

3,5

PRIMARY PREVENTION

SECONDARY PREVENTION

Figure 6 Comparison of risk assessments in asymptomatic apparently healthysubjects (primary prevention) and patients with established chronic coro-

nary syndromes (secondary prevention). Note that in asymptomatic subjects (left panel), SCORE estimates 10 year cardiovascular mortality, while in

symptomatic patients (right panel), annual cardiac mortality is estimated. CCS = chronic coronary syndromes; SCORE = Systematic COronary Risk

Evaluation.

ESC Guidelines 21

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angina and LV systolic dysfunction in a pattern that indicates CAD are

also at high risk of cardiac mortality.

101

ICA for risk stratification will

only be required in a selected subgroup of patients and additional FFR

may be required for event risk stratification as appropriate (Figure 4 ).

Risk assessment in patients with HF and LV dysfunction, asymptomatic

patients with known CAD, and patients with recurrent symptoms

after previous coronary intervention is discussed in sections 4 and 5.

3.1.6.1 Definition of levels of risk

In patients with established CCS, the risk of annual cardiac mortality is

used to describe the event risk. As in the previous version of the

Guidelines,

high event risk is defined as a cardiac mortality rate >3%

per year and low event risk as a cardiac mortality rate <1% per year.

The definitions of high event risk based on findings of diagnostic tests in

symptomatic patients or in patients with established CCS are shown in

Table 6.

Notably, the level of risk is different from the risk assessment based

onSCOREinasymptomaticindividualswithoutdiabeteswhoare

apparently healthy (see section 7 ). SCORE defines 10 year cardiovas-

cular mortality in asymptomatic subjects. Differences in these risk-

assessment tools and the scales are illustrated in Figure 6 . The findings

of different test modalities that correspond to high event risk are pre-

sented in Table 6 and are discussed in more detail in the

Supplementary Data (sections 1.1 and 1.2).

102104

For all non-invasive

tests presented in Table 6 , a normal test result is associated with a low

event risk.

105

Recommendations on risk assessment

Recommendations Class

Level

Risk stratiﬁcation is recommended based on clinical assessment and the result of the diagnostic test initially employed to

diagnose CAD.

6, 75,102,103

Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. IC

Risk stratiﬁcation, preferably using stress imaging or coronary CTA (if permitted by local expertise and availability), or

alternatively exercise stress ECG (if signiﬁcant exercise can be performed and the ECG is amenable to the identiﬁcation

of ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.

6, 75,102,106

In symptomatic patients with a high-risk clinical proﬁle, ICA complemented by invasive physiological guidance (FFR) is rec-

ommended for cardiovascular risk stratiﬁcation, particularly if the symptoms are responding inadequately to medical treat-

ment and revascularization is considered for improvement of prognosis.

104,107

In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended

for patients on medical treatment, in whom non-invasive risk stratiﬁcation indicates a high event risk and revascularization

is considered for improvement of prognosis.

104,107

ICA complemented by invasive physiological guidance (FFR) should be considered for risk-stratiﬁcation purposes in

patients with inconclusive or conﬂicting results from non-invasive testing.

IIa B

If coronary CTA is available for event risk stratiﬁcation, additional stress imaging should be performed before the referral

of a patient with few/no symptoms for ICA.

108,109

IIa B

Echocardiographic assessment of global longitudinal strain provides incremental information to LVEF and may be consid-

ered when LVEF is >35%.

110114

IIb B

Intravascular ultrasound may be considered for the risk stratiﬁcation of patients with intermediate LM stenosis.

115,116

IIb B

ICA is not recommended solely for risk stratiﬁcation. III C

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional ﬂow reserve; ICA = invasive coronary angiography;

iwFR = instantaneous wave-free ratio; LM = left main; LV = left ventricular; LVEF = LV ejection fraction.

Class of recommendation.

Level of evidence.

22 ESC Guidelines

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3.2 Lifestyle management

3.2.1 General management of patients with coronary

artery disease

General management of CCS aims to reduce symptoms and

improve prognosis through appropriate medications and inter-

ventions, and to control risk factors including lifestyle behaviours.

Optimal medical therapy in the COURAGE (Clinical Outcomes

Utilizing Revascularization and Aggressive Drug Evaluation) trial

included the promotion of medication adherence, behavioural

counselling, and support for the managing lifestyle risk factors

delivered by nurse case managers.

117

Achievement of optimal

management may be best accomplished through a multidiscipli-

nary team approach that can provide tailored and flexible support

to patients.

Patient-reported outcome measures can provide relevant and

systematic information about patients' symptoms, functioning, and

concerns. Patient-reported outcome measures are increasingly

being implemented sequentially in healthcare, and have been

shown to improve clinical care and patient experiences, communi-

cation between providers and patients (including sensitive sub-

jects), save time in consultations, and improve provider

satisfaction.

118

3.2.2 Lifestyle modification and control of risk factors

Implementing healthy lifestyle behaviours decreases the risk of subse-

quent cardiovascular events and mortality, and is additional to appro-

priate secondary prevention therapy. Lifestyle recommendations and

interventions are described in more detail in the 2016 ESC

Guidelines on CVD prevention in clinical practice.

Lifestyle factors

are important and the implementation of healthy behaviours (includ-

ing smoking cessation, recommended physical activity, a healthy diet,

and maintaining a healthy weight; see Table 7 ) significantly decreases

the risk of future cardiovascular events and death, even when con-

trolling for evidence-based secondary prevention therapy and inter-

ventions.

119122

Benefits are evident as early as 6 months after an

index event.

119

Primary care providers have an important role to play in preven-

tion. The primary care arm of the EUROACTION cluster random-

ized trial demonstrated that a nurse-co-ordinated programme in

primary care was more effective in helping patients achieve lifestyle

and risk-factor goals than usual care.

123

Practice nurses in the

Netherlands were found to be as effective as general practitioners in

decreasing cardiovascular risk in another randomized study.

123

3.2.2.1 Smoking

Smoking cessation improves the prognosis in patients with CCS,

including a 36% risk reduction in mortality for those who quit.

124

Measures to promote smoking cessation include brief advice, coun-

selling and behavioural interventions, and pharmacological therapy

including nicotine replacement. Patients should also avoid passive

smoking.

Brief advice, relative to no treatment, doubles the likelihood of

smoking cessation in the short-term, but more intensive advice and

support (behavioural interventions, telephone support, or self-help

measures) is more effective than brief advice, especially if continued

over 1 month.

125,126

All forms of nicotine-replacement therapy,

bupropion, and varenicline are more effective in increasing smoking

cessation than control, and combining behavioural and pharmacologi-

cal approaches is effective and highly recommended.

125

A network

meta-analysis of 63 clinical trials (including eight trials in CVD

patients) found no increase in major adverse cardiovascular events

linked to nicotine-replacement therapy, bupropion, or varenicline.

127

Nicotine-replacement therapy was associated with minor events

such as arrhythmias and angina, and bupropion appeared to have a

protective effect against major adverse cardiovascular events.

127

The

use of e-cigarettes is considered to be a reduced-harm alternative to

conventional cigarettes, but they are not harm-free. Newer devices

can deliver higher nicotine contents, and e-cigarettes emit other con-

stituents such as carbonyls and fine and ultrafine particulates.

128

Although previous systematic reviews have found very limited and

inconsistent evidence that e-cigarettes (primarily first-generation

devices) are useful in improve smoking cessation compared with pla-

cebo or nicotine-replacement therapy, a recent large clinical trial

found e-cigarettes to be more effective than nicotine-replacement

therapy in smoking cessation.

129133

In this randomised trial of 886

smokers, those assigned to e-cigarettes had a sustained 1 year absti-

nence rate of 18% compared with 9.9% for nicotine-replacement

therapy [relative risk, 1.83; 95% confidence interval (CI) 1.30 to 2.58;

P<0.001].

133

In clinical encounters with smokers, clinicians should follow the

'Five As': ask about smoking, advise to quit, assess readiness to quit,

assist with smoking cessation (pharmacological support and referral

for behavioural counselling), and arrange follow-up (Figure 7 ).

Table 7 Lifestyle recommendations for patients with chronic coronary syndromes

Lifestyle factor

Smoking cessation Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.

Healthy diet Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.

Physical activity 30 - 60 min moderate physical activity most days, but even irregular activity is beneﬁcial.

Healthy weight Obtain and maintain a healthy weight (<25 kg/m

), or reduce weight through recommended energy intake and increased

physical activity.

Other Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.

ESC Guidelines 23

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3.2.2.2 Diet and alcohol

Unhealthy diets are a leading contributor to CAD and its progres-

sion, and changes to healthy eating patterns in patients with CCS

have resulted in a reduction in mortality and cardiovascular

events

134

(recommended diet characteristics are detailed in

Table 8 ).

A Mediterranean dietary pattern high in fruit, vegetables,

legumes, fibre, polyunsaturated fats, nuts, and fish, avoiding or lim-

iting refined carbohydrates, red meat, dairy, and saturated fat, is

advocated.

135138

Although light-to-moderate alcohol intake

(1 2 drinks per day) does not increase risk of MI, levels >100 g

per week were associated with higher all-cause and other CVD

mortality in a large individual-data meta-analysis.

139

The Global

Burden of Disease 1990 2016 analysis concluded that zero alco-

hol intake was the level at which risk for death and disability was

minimized.

140

3.2.2.3 Weight management

In a population-based study, lifetime risk of incident CVD, and car-

diovascular morbidity and mortality, were higher in those who

were overweight or obese compared with those with a normal

BMI (20 - 25 kg/m

). Obesity was associated with a shorter overall

lifespan, and overweight was associated with developing CVD at

an earlier age.

143

Waist circumference is a marker of central obe-

sity and is strongly associated with developing CVD and diabetes.

Waist circumference < _94cmformen(<90cmforSouthAsian

and Asian men) and < _80 cm for women is recommended.

In subjects with CAD, intentional weight loss is associated with a

significantly lower risk of adverse clinical outcomes.

144

Although

there has been much argument regarding the relative benefits of low-

fat vs. low-carbohydrate diets, Gardner et al.

145

found similar weight

loss and benefits in patients randomized to either healthy low-fat or

low-carbohydrate diets. This finding held, regardless of patients' gen-

otype patterns and baseline insulin secretion. Healthy diets with

energy intake limited to the amount needed to obtain and maintain a

healthy weight (BMI <25 kg/m

), and increasing physical activity, are

recommended for weight management.

3.2.2.4 Physical activity

Exercisehas been referred to as a 'polypill' due to its numerous bene-

ficial effects on cardiovascular risk factors and cardiovascular system

physiology.

146,147

Exercise improves angina through enhanced oxy-

gen delivery to the myocardium, and increasing exercise capacity is

an independent predictor of increased survival among men and

women with CCS, even among those with a regimen consistent with

evidence-based management.

122,147,148

Every 1 mL/kg/min increase in exercise peak oxygen consumption

was associated with a 1417% reduction of risk for cardiovascular

and all-cause death in women and men.

122

Physical activity recommendations for patients with CCS are

30 60 min of moderate-intensity aerobic activity > _5 days per

week.

147

Even irregular leisure-time physical activity decreases mortal-

ity risk among previously sedentary patients,

149

and increasing activity

is associated with lower cardiovascular mortality.

150

Previously seden-

tary patients will need support to work up to 30 60 min most days,

reassurance that exercise is beneficial, and education regarding what

to do if angina occurs while being active. Resistance exercises maintain

muscle mass, strength, and function and, with aerobic activity, have

benefits regarding insulin sensitivity and control of lipids and BP.

3.2.2.5 Cardiac rehabilitation

Exercise-based cardiac rehabilitation has consistently demonstrated

its effectiveness in reducing cardiovascular mortality and hospitaliza-

tions compared with no exercise controls in patients with CAD, and

this benefit persists into the modern era.

151153

Most patients partici-

pating in cardiac rehabilitation are referred following an acute MI or

after revascularization, with 0 - 24% of patients found to be referred

for CCS in 12 European countries.

154

Importantly, the benefits of car-

diac rehabilitation occur across diagnostic categories.

151153

3.2.2.6 Psychosocial factors

Patients with heart disease have a two-fold increased risk of mood

and anxiety disorders compared with people without heart dis-

ease.

155,156

Psychosocial stress, depression, and anxiety are associ-

ated with worse outcomes, and make it difficult for patients to make

positive changes to their lifestyles or adhere to a therapeutic regimen.

©ESC 2019

Assist with

smoking

cessation

Arrange

follow-up

Advise to

quit

Assess

readiness

to quit

Ask about

smoking

5As

Figure 7 The five As of smoking cessation.

Table 8 Healthy diet characteristics

134,137,141,142

Characteristics

Increase consumption of fruits and vegetables (>_200 g each per day).

35 45 g of ﬁbre per day, preferably from wholegrains.

Moderate consumption of nuts (30 g per day, unsalted).

1 2 servings of ﬁsh per week (one to be oily ﬁsh).

Limited lean meat, low-fat dairy products, and liquid vegetable oils.

Saturated fats to account for <10% of total energy intake; replace with

polyunsaturated fats.

As little intake of trans unsaturated fats as possible, preferably no intake

from processed food, and <1% of total energy intake.

<_5 6 g of salt per day.

If alcohol is consumed, limiting intake to <_100 g/week or <15 g/day is

recommended.

Avoid energy-dense foods such as sugar-sweetened soft drinks.

24 ESC Guidelines

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The ESC Prevention Guidelines recommend assessment for psycho-

social risk factors.

Clinical trials have shown that psychological (e.g.

counselling and/or cognitive behavioural therapy) and pharmacologi-

cal interventions have a beneficial effect on depression, anxiety, and

stress, with some evidence of a reduction in cardiac mortality and

events compared with placebo.

157159

3.2.2.7 Environmental factors

Air pollutants are estimated to be one of the 10 leading risk factors for

global mortality. Exposure to air pollution increases risk of MI, as well

as hospitalization and death from heart failure, stroke, and arrhyth-

mia.

160

Patients with CCS should avoid heavily traffic-congested areas.

Air purifiers with high-efficiency particulate air ('HEPA') filters reduce

indoor pollution, and wearing N95 respirator face masks in heavily pol-

luted areas has been shown to be protective.

160

Environmental noise

also increases the risk of CVD.

161

Policies and regulations that reduce

air pollution and environmental noise should be supported, and

patients should be advised about these risks.

3.2.2.8 Sexual activity

Patients with CCS often worry about the cardiovascular risk associ-

ated with sexual activity and/or experience sexual dysfunction.

162

The risk of triggering sudden death or an acute MI is very low, espe-

cially when sexual activity is with a stable partner in a familiar environ-

ment without stress, or excessive intake of food or alcohol

beforehand.

163,164

Although sexual activity transiently increases the

risk of MI, it is the cause of <1% of acute MIs and <11.7% of sudden

deaths occur during sexual activity.

164

The energy expenditure during

sexual activity is generally low-to-moderate (3- 5 metabolic equiva-

lents) and climbing two flights of stairs is often used as an equivalent

activity in terms of energy expended.

163,164

Regular physical activity

decreases the risk of adverse events during sexual activity.

165

Sexual

dysfunction in patients with CCS includes decreased libido and sexual

activity, and a high prevalence of erectile dysfunction. Sexual dysfunc-

tion may be caused by underlying vascular conditions, psychosocial

factors, specific medications, number of medications, and changes in

relationships.

166

Thiazide diuretics and beta-blockers (except nebivo-

lol) may negatively influence erectile function, but studies published

since 2011 have not found a consistent relationship between most

contemporary cardiovascular medications and erectile dysfunc-

tion.

162,164,165

Phosphodiesterase-5 inhibitors to treat erectile dys-

function are generally safe in CCS patients, but should not be used in

those taking nitrates.

164

Healthcare providers should ask patients

about sexual activity, and offer advice and counselling.

3.2.2.9 Adherence and sustainability

Adherence to lifestyle modifications and to medications is a chal-

lenge. A systematic review of epidemiological studies indicated that a

substantial proportion of patients do not adhere to cardiovascular

medications, and that 9% of cardiovascular events in Europe were

attributable to poor adherence.

167

In older men with ischaemic heart

disease, greater adherence to medication guidelines appears to be

positively associated with better clinical outcomes, independent of

other conditions.

168

Polypharmacy plays a negative role in adherence

to treatment,

169

and complexity of drug regimen is associated with

non-adherence and higher rates of hospitalizations.

170

Drug prescrip-

tions should prioritize medications that have proved their benefit

with the highest level of evidence and those for whom the amplitude

of benefit is largest. Simplifying medication regimens may help, and

there is some evidence of benefits of cognitive educational strategies,

electronically monitored feedback, and support by nurse case manag-

ers. Medication reviews by primary care providers may be helpful in

patients with multiple comorbidities to minimize the risk of adverse

interactions and to simplify medication regimens.

117,171173

Promoting behaviour change and medication adherence should be

part of each clinical encounter in primary care and specialist follow-up,

emphasising its importance, referring for support when needed, and con-

gratulating patients for their achievements. Long-term support (intensive

inthefirst6months,thenevery6monthsfor3years)intheGOSPEL

(Global secondary prevention strategies to limit event recurrence after

myocardial infarction) trial resulted in significant improvements in risk

factors, and decreases in several clinical mortality and morbidity end-

points.

121

The Multicenter Lifestyle Demonstration Project showed that

CCS patients could make intensive lifestyle changes and improve their

risk factors and fitness, with changes sustained at 12 months.

174

3.2.2.10 Influenza vaccination

An annual influenza vaccination can improve prevention of acute MI

in patients with CCS,

175,176

change HF prognosis,

177

and decrease

cardiovascular mortality in adults aged >_65 years.

178 180

Therefore,

annual influenza vaccination is recommended for patients with CAD,

especially in the elderly.

Recommendations on lifestyle management

Recommendations Class

Level

Improvement of lifestyle factors in addition

to appropriate pharmacological management is

recommended.

119122,124,148153

Cognitive behavioural interventions are rec-

ommended to help individuals achieve a

healthy lifestyle.

181183

Exercise-based cardiac rehabilitation is recom-

mended as an effective means for patients

with CCS to achieve a healthy lifestyle and

manage risk factors.

151153

Involvement of multidisciplinary healthcare pro-

fessionals (e.g. cardiologists, GPs, nurses, dieti-

cians, physiotherapists, psychologists, and

pharmacists) is recommended.

121,123,181, 184

Psychological interventions are recommended

to improve symptoms of depression in

patients with CCS.

126,157

Annual inﬂuenza vaccination is recommended

for patients with CCS, especially in the

elderly.

175,176,178,179,185187

CCS = chronic coronary syndrome; GPs = general practitioners.

Class of recommendation.

Level of evidence.

ESC Guidelines 25

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3.3 Pharmacological management

The aims of pharmacological management of CCS patients are to

reduce angina symptoms and exercise-induced ischaemia, and topre-

vent cardiovascular events.

Immediate relief of anginal symptoms, or the prevention of symp-

toms under circumstances likely to elicit angina, is usually obtained

with rapidly acting formulations of nitroglycerin. Anti-ischaemic

drugs—but also lifestyle changes, regular exercise training, patient

education, and revascularization—all play a role in minimizing or

eradicating symptoms over the long-term (long-term prevention).

Prevention of cardiovascular events targets MI and death associ-

ated with CAD, and focuses primarily on reducing the incidence of

acute thrombotic events and the development of ventricular dysfunc-

tion. Strategies include pharmacological and lifestyle interventions, as

detailed in the 2016 European Guidelines on CVD prevention in clini-

cal practice.

3.3.1 Anti-ischaemic drugs

3.3.1.1 General strategy

Optimal treatment can be defined as the treatment that satisfactorily

controls symptoms and prevents cardiac events associated with CCS,

with maximal patient adherence and minimal adverse events.

188 191

However, there is no universal definition of an optimal treatment in

patients with CCS, and drug therapies must be adapted to each

patient's characteristics and preferences.

192

Initial drug therapy usually

consists of one or two antianginal drugs, as necessary, plus drugs for

secondary prevention of CVD.

193

The initial choice of antianginal

drug(s) depends on the expected tolerance related to the individual

patient's profile and comorbidities, potential drug interactions with co-

administered therapies, the patient's preferences after being informed

of potential adverse effects, and drug availability. Whether combination

therapy with two antianginal drugs [e.g. a beta-blocker and a calcium

channel blocker (CCB)] is superior to monotherapy with any class of

antianginal drug in reducing clinical events remains unclear.

194197

Beta-adrenergic blockers or CCBs are recommended as the first

choice, although no RCT to date has compared this strategy to an

alternative strategy using initial prescription of other anti-ischaemic

drugs, or the combination of a beta-blocker and a CCB.

191,195

The

results of a network meta-analysis of 46 studies and 71 treatment com-

parisons supported the initial combination of a beta-blocker and a

CCB.

198

The same meta-analysis suggested that several second-line

add-on anti-ischaemic drugs (long-acting nitrates, ranolazine, trimetazi-

dine, and, to a lesser extent, ivabradine) may prove beneficial in combi-

nation with a beta-blocker or a CCB as first-line therapy, while no data

were available for nicorandil. However, it should be noted that the

study pooled RCTs using endpoints of nitrate use, angina frequency,

time to angina or to ST-segment depression, and total exercise time,

and no study or meta-analysis has yet assessed with sufficient power

the influence of combining a beta-blocker or a CCB with a second-line

anti-ischaemic drug on morbidity or mortality events.

198

Regardless of

the initial strategy, response to initial antianginal therapy should be

reassessed after 2 4 weeks of treatment initiation.

3.3.1.2 Available drugs

Anti-ischaemic drugs have proved benefits regarding symptoms asso-

ciated with myocardial ischaemia but do not prevent cardiovascular

events in most patients with CCS. Supplementary Table 3 in the

Supplementary Data summarizes the principal major side effects,

contraindications, drug drug interactions, and precautions relating

to anti-ischaemic drugs. Supplementary Table 2 summarizes the main

mechanisms of action of anti-ischaemic drugs.

3.3.1.2.1 Nitrates.

Short-acting nitrates for acute effort angina

Sublingual and spray nitroglycerin formulations provide immediate

relief of effort angina. Spray nitroglycerin acts more rapidly than sub-

lingual nitroglycerin.

199

At the onset of angina symptoms, the patient

should rest in a sitting position (standing promotes syncope, and lying

down enhances venous return and preload) and take nitroglycerin

(0.3 0.6 mg tablet sublingually and not swallowed, or 0.4 mg spray

to the tongue and not swallowed or inhaled) every 5 min until the

pain disappears, or a maximum of 1.2 mg has been taken within 15

min. During this time frame, if angina persists, immediate medical

attention is needed. Nitroglycerin can be administered for prophy-

laxis before physical activities known to provoke angina. Isosorbide

dinitrate (5 mg sublingually) has a slightly slower onset of action than

nitroglycerin due to hepatic conversion to mononitrate. The effect of

isosorbide dinitrate may last <_1 h if the drug is taken sublingually or

persist for several hours if the drug is taken by oral ingestion.

Long-acting nitrates for angina prophylaxis

Long-acting nitrate formulations (e.g. nitroglycerin, isosorbide dini-

trate, and isosorbide mononitrate) should be considered as second-

line therapy for angina relief when initial therapy with a beta-blocker or

non-dihydropyridine (non-DHP) CCB is contraindicated, poorly toler-

ated, or insufficient to control symptoms. In fact, there is a paucity of

data comparing nitrates with beta-blockers or CCB from which to

draw firm conclusions about their relative efficacies.

200

When taken

over a prolonged period, long-acting nitrates provoke tolerance with

loss of efficacy, which requires prescription of a nitrate-free or nitrate-

low interval of  10 14 h.

201

Nitroglycerin can be administered orally

or transdermally through slow-release patch systems. Bioavailability of

isosorbide dinitrate depends on the interindividual variability in hepatic

conversion and is generally lower than the bioavailability of isosorbide

mononitrate (its active metabolite), which is 100% bioavailable.

Titration of dose is essential with all formulations to obtain the maximal

control of symptoms at a tolerable dose. Discontinuation should be

tapered and not abrupt to avoid a rebound increase in angina.

202

The

most common side effects are hypotension, headache, and flushing.

Contraindications include hypertrophic obstructive cardiomyopathy,

severe aortic valvular stenosis, and co-administration of phosphodies-

terase inhibitors (e.g. sildenafil, tadalafil, or vardenafil) or riociguat.

3.3.1.2.2 Beta-blockers. The dose of beta-blockers should be adjusted

to limit the heart rate to 55 60 b.p.m. (beats per minute) at

rest.

203,204

Discontinuation should be tapered and not abrupt. Beta-

blockers can be combined with DHP CCBs to reduce DHP-induced

tachycardia, but with uncertain incremental clinical value.

205208

Caution is warranted when a beta-blocker is combined with verapa-

mil or diltiazem due to the potential for developing worsening of HF,

excessive bradycardia, and/or atrioventricular block. Combination of

a beta-blocker with a nitrate attenuates the reflex tachycardia of

the latter. The principal side effects of beta-blockers are fatigue,

depression, bradycardia, heart block, bronchospasm, peripheral

26 ESC Guidelines

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vasoconstriction, postural hypotension, impotence, and masking of

hypoglycaemia symptoms.

In certain patients with recent MI and those with chronic HF with

reduced ejection fraction, beta-blockers have been associated with a

significant reduction in mortality and/or cardiovascular events,

209215

but the protective benefit in patients with CAD without prior MI or

HF is less well established and lacks placebo-controlled trials.

216

retrospective analysis of 21 860 matched patients from the REACH

(REduction of Atherothrombosis for Continued Health) Registry

showed no reduction in cardiovascular mortality with beta-blockers

in patients with either CAD with risk factors only, known prior MI, or

known CAD without MI.

217

In a retrospective national registry of

755 215 patients aged >_65 years with a history of CAD without prior

MI or HF with reduced ejection fraction undergoing elective PCI,

beta-blocker use at discharge was not associated with any reduction

in cardiovascular morbidity or mortality at 30 day and 3 year follow-

up.

218

However, in patients with or without previous MI undergoing

CABG, beta-blockers were associated with lower risk of long-term

mortality and adverse cardiovascular events.

219

Other observational

studies and meta-analyses have questioned the benefit of long-term

(>1 year) beta-blocker therapy in patients with a previous

MI.

216,220 224

This is still a matter for debate,

225

and uncertainties

remain on the comparative role of beta-blockers and angiotensin-

converting enzyme (ACE) inhibitors.

3.3.1.2.3 Calcium channel blockers. While CCBs improve symptoms

and myocardial ischaemia, they have not been shown to reduce

major morbidity endpoints or mortality in patients with

CCS.

192,226228

NON-DIHYDROPYRIDINE AGENTS ( HEART RATE - LOWERING CALCIUM CHANNEL

BLOCKERS )

Verapamil . Verapamil has a large range of approved indications,

including all varieties of angina (effort, vasospastic, and unstable),

supraventricular tachycardias, and hypertension. Indirect evidence

suggests good safety but with risks of heart block, bradycardia, and

HF. Compared with metoprolol, the antianginal activity was simi-

lar.

229

Compared with atenonol in hypertension with CAD, verapa-

mil is associated with fewer cases of diabetes, fewer anginal

attacks,

230

and less psychological depression.

231

Beta-blockade com-

bined with verapamil is not advised (due to risk of heart block).

Diltiazem. Diltiazem, with its low-side effect profile, has advantages

compared with verapamil in the treatment of effort angina. Like vera-

pamil, it acts by peripheral vasodilation, relief of exercise-induced

coronary constriction, a modest negative inotropic effect, and sinus

node inhibition. There have been no outcome studies comparing dil-

tiazem and verapamil.

In some selected patients, non-DHP agents may be combined with

beta-blockers for the treatment of angina. However, on such occa-

sions they must be used under closemonitoring of patients' tolerance

regarding excessive bradycardia or signs of HF. Use of non-DHP

CCBs in patients with LV dysfunction is not advised.

DIHYDROPYRIDINE AGENTS

Long-acting nifedipine. This agent is a powerful arterial vasodilator with

few serious side effects. Long-acting nifedipine has been especially

well tested in hypertensive anginal patients when added to beta-

blockade.

232

In the large placebo-controlled ACTION (A Coronary

disease Trial Investigating Outcome with Nifedipine gastrointestinal

therapeutic system) trial, addition of long-acting nifedipine [60 mg

o.d. (once a day)] to conventional treatment of angina had no effect

on major cardiovascular event-free survival. Long-acting nifedipine

proved to be safe, and reduced the need for coronary angiography

and cardiovascular interventions.

232

Relative contraindications to

nifedipine are few (severe aortic stenosis, hypertrophic obstructive

cardiomyopathy, or HF), and careful combination with beta-blockade

is usually feasible and desirable. Vasodilatory side effects include

headache and ankle oedema.

Amlodipine. The very long half-life of amlodipine and its good toler-

ability make it an effective once-a-day antianginal and antihyperten-

sive agent, setting it apart from drugs that are taken either twice or

three times daily. Side effects are few, mainly ankle oedema. In

patients with CCS and normal BP ( 75% receiving a beta-blocker),

amlodipine 10 mg/day reduced coronary revascularizations and hos-

pitalizations for angina in a 24 month trial.

233

Exercise-induced ischae-

mia is more effectively reduced by amlodipine, 5 mg titrated to

10 mg/day, than by the beta-blocker atenolol, 50 mg/day, and their

combination is even better.

234

However, the CCB beta-blocker

combination is often underused, even in some studies reporting 'opti-

mally treated' stable effort angina.

3.3.1.2.4 Ivabradine. Ivabradine has been reported to be non-inferior

to atenolol or amlodipine in the treatment of angina and ischaemia in

patients with CCS.

235,236

Adding ivabradine 7.5 mg b.i.d. [bis in die

(twice a day)] to atenolol therapy gave better control of heart rate

and anginal symptoms.

237

In 10 917 patients with limiting previous

angina enrolled in the morbidity mortality evaluation of the

BEAUTIFUL (I

Inhibitor Ivabradine in Patients With Coronary Artery

Disease and Left Ventricular Dysfunction) trial, ivabradine did not

reduce the composite primary endpoint of cardiovascular death, hos-

pitalization with MI, or HF.

238

Also, in the SIGNIFY (Study Assessing

the Morbidity Mortality Benefits of the I

Inhibitor Ivabradine in

Patients with Coronary Artery Disease) study, consisting of 19 102

patients with CAD without clinical HF and a heart rate >_70 b.p.m.,

there was no significant difference between the ivabradine group and

the placebo group in the incidence of the primary composite end-

point of death from cardiovascular causes or non-fatal MI.

239

Ivabradine was associated with an increase in the incidence of the pri-

mary endpoint among 12 049 patients with activity-limiting angina but

not among those without activity-limiting angina ( P=0.02 for interac-

tion). In 2014, the European Medicines Agency issued recommenda-

tions to reduce the risk of bradycardia and placed ivabradine under

additional monitoring.

240

In aggregate, these results support the use

of ivabradine as a second-line drug in patients with CCS.

3.3.1.2.5 Nicorandil. Nicorandil is a nitrate derivative of nicotinamide,

with antianginal effects similar to those of nitrates or beta-block-

ers.

241244

Side effects include nausea, vomiting, and potentially

severe oral, intestinal, and mucosal ulcerations.

245

In the placebo-controlled IONA (Impact Of Nicorandil in Angina)

trial (n = 5126), nicorandil significantly reduced the composite of cor-

onary heart disease (CHD) death, non-fatal MI, or unplanned hospital

admission for suspected anginal symptoms in patients with CCS, but

there was no effect on death from ischaemic heart disease or non-

ESC Guidelines 27

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fatal MI.

246

These results support the use of nicorandil as a second-

line drug in patients with CCS.

3.3.1.2.6 Ranolazine. Ranolazine is a selective inhibitor of the late

inward sodium current. Side effects include dizziness, nausea, and

constipation. In addition, ranolazine increases QTc, and should there-

fore be used carefully in patients with QT prolongation or on QT-

prolonging drugs.

In a placebo-controlled trial of 6560 patients with non-ST-segment

elevation ACS, the addition of ranolazine to standard treatment did

not prove effective in reducing the primary efficacy endpoint of cardi-

ovascular death, MI, or recurrent ischaemia.

247

However, in the rela-

tively large subgroup of patients with chronic angina (n = 3565),

significant reductions in recurrent ischaemia, worsening angina, and

intensification of antianginal therapy were observed.

248

In another

placebo-controlled trial of patients with diabetes and CAD receiving

one or two antianginal drugs, ranolazine reduced angina and sublin-

gual nitroglycerin use with good tolerability.

249

In the RIVER-PCI

(Ranolazine for Incomplete Vessel Revascularization Post-

Percutaneous Coronary Intervention) trial, ranolazine did not reduce

the composite of ischaemia-driven revascularization or

hospitalization without revascularization in 2651 patients with a his-

tory of chronic angina and incomplete revascularization after PCI,

including those with and without PCI for a CAD indication, nor did it

reduce angina symptoms at 1 year.

250,251

These results support the use of ranolazine as a second-line drug

in CCS patients with refractory angina despite commonly used anti-

anginal agents such as beta-blockers, CCBs, and/or long-acting

nitrates. Conversely, there is a lack of evidence to support the use of

ranolazine in patients with CCS following PCI with incomplete

revascularization.

3.3.1.2.7 Trimetazidine. Trimetazidine appears to have a haemodynami-

cally neutral side effect profile.

252

Trimetazidine (35 mg b.i.d.) added to

beta-blockade (atenolol) improved effort-induced myocardial ischae-

mia, as reviewed by the European Medicines Agency in June

2012.

253,254

It remains contraindicated in Parkinson's disease and

motion disorders, such as tremor (shaking), muscle rigidity, walking dis-

orders, and restless leg syndrome. A 2014 meta-analysis of 13, mostly

Chinese, studies consisting of 1628 patients showed that treatment

with trimetazidine on top of other antianginal drugs was associated

with a smaller weekly mean number of angina attacks, lower weekly

ESC 2019

Standard

Therapy

High heart rate

(e.g. >80 b.p.m)

Low heart rate

(e.g. <50 b.p.m)

LV dysfunction

or heart failure

Low blood

pressure

BB or CCB

step BB or

non-DHP-CCB DHP-CCB BB

Low-dose BB or

Low-dose non-

DHP-CCB

BB + DHP-CCB

step BB and

non-DHP-CCB LAN Add LAN or

ivabradine

Add low-dose

LAN

Add 2

line drug3

step Add ivabradine DHP-CCB + LAN Add another

line drug

Add ivabradine,

ranolazine, or

trimetazidine

step

Add nicorandil,

ranolazine or

trimetazidine

Figure 8 Suggested stepwise strategy for long-term anti-ischaemic drug therapy in patients with chronic coronary syndromes and specific baseline char-

acteristics. BB = beta-blocker; b.p.m. = beats per minute; CCB = [any class of] calcium channel blocker; DHP-CCB = dihydropyridine calcium channel

blocker; HF = heart failure;LAN = long-acting nitrate; LV = left ventricular; NDHP-CCB: non-dihydropyridine calcium channel blocker.

Combination of a

BB with a DHP-CCB should be considered as a first step; combination of a BBor a CCB with a second-line drug may be considered as a first step.

28 ESC Guidelines

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nitroglycerin use, longer time to 1 mm ST-segment depression,

higher total work, and longer exercise duration at peak exercise than

treatment with the other antianginal drugs for stable angina pecto-

ris.

255

These results support the use of trimetazidine as a second-line

drug in patients with CCS whose symptoms are not adequately con-

trolled by, or who are intolerant to, other medicines for angina

pectoris.

3.3.1.2.8 Allopurinol. In 2010, a randomized crossover study of 65

patients with CAD showed that allopurinol 600 mg/day increased

times to ST-segment depression and to angina.

256

An observational

study of 29 298 episodes of incident allopurinol use found an associa-

tion of allopurinol use with a reduction in the risk of incident MI in

the elderly, particularly when used for >2 years.

257

However, the

role of allopurinol in reducing clinical events in CVD remains

unclear.

258

A stepwise strategy for anti-ischaemic drug therapy in CCS is pro-

posed, depending on some baseline patient characteristics (Figure 8 ).

Incomplete responses or poor tolerance at each step justify moving

to the next step. The strategy must be adapted to each patient's

characteristics and preferences, and does not necessarily follow the

steps indicated in the figure.

3.3.1.3 Patients with low blood pressure

In patients with low BP, it is recommended to start antianginal drugs at

very low doses, with preferential use of drugs with no or limited effects

on BP. A low-dose beta-blocker or low-dose non-DHP-CCB can be

tested first under close monitoring of tolerance. Ivabradine (in patients

with sinus rhythm), ranolazine, or trimetazidine can also be used.

3.3.1.4 Patients with low heart rate

Increased heart rate correlates linearly with cardiovascular

events, and the benefit of heart-rate reduction as a treatment

goal in subgroups of CCS patients has been demonstrated using

various drugs.

203,259 261

However, in patients with baseline bra-

dycardia (e.g. heart rate <60 b.p.m.) heart rate-lowering drugs

(beta-blockers, ivabradine, and heart-rate lowering CCBs) should

be avoided or used with caution, and—if needed—started at very

low doses. Antianginal drugs without heart rate-lowering effects

should preferably be given.

Recommendations on anti-ischaemic drugs in patients with chronic coronary syndromes

Recommendations Class

Level

General considerations

Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with

drug(s) for event prevention. IC

It is recommended that patients are educated about the disease, risk factors, and treatment strategy. IC

Timely review of the patient's response to medical therapies (e.g. 2 4 weeks after drug initiation) is recommended.

262

Angina/ischaemia

relief

Short-acting nitrates are recommended for immediate relief of effort angina.

195,263

First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms.

205,264

If angina symptoms are not successfully controlled on a beta-blocker or a CCB, the combination of a beta-blocker with a

DHP-CCB should be considered. IIa C

Initial ﬁrst-line treatment with the combination of a beta-blocker and a DHP-CCB should be considered.

194,198,264

IIa B

Long-acting nitrates should be considered as a second-line treatment option when initial therapy with a beta-blocker and/or a

non-DHP-CCB is contraindicated, poorly tolerated, or inadequate to control angina symptoms.

200,201

IIa B

When long-acting nitrates are prescribed, a nitrate-free or low-nitrate interval should be considered to reduce tolerance.

201

IIa B

Nicorandil,

241244,246

ranolazine,

248,265

ivabradine,

235237

or trimetazidine

252,255

should be considered as a second-line treat-

ment to reduce angina frequency and improve exercise tolerance in subjects who cannot tolerate, have contraindications to,

or whose symptoms are not adequately controlled by beta-blockers, CCBs, and long-acting nitrates.

IIa B

In subjects with baseline low heart rate and low BP, ranolazine or trimetazidine may be considered as a ﬁrst-line drug to

reduce angina frequency and improve exercise tolerance. IIb C

In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine,

and trimetazidine) may be considered for ﬁrst-line treatment according to heart rate, BP, and tolerance.

198

IIb B

Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy

266

or co-administration of phos-

phodiesterase inhibitors.

267

III B

BP = blood pressure; CCB = calcium channel blocker; CCS = chronic coronary syndromes; DHP-CCB = dihydropyridine calcium channel blocker.

Class of recommendation.

Level of evidence.

No demonstration of beneﬁt on prognosis.

ESC Guidelines 29

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3.3.2 Event prevention

3.3.2.1 Antiplatelet drugs

Platelet activation and aggregation is the driver for symptomatic cor-

onary thrombosis, forming the basis for the use of antiplatelet drugs

in patients with CCS in view of a favourable balance between the pre-

vention of ischaemic events and increased risk of bleeding. Dual anti-

platelet therapy (DAPT) with aspirin and an oral P2Y

inhibitor is

the mainstay of antithrombotic therapy after MI and/or PCI.

3.3.2.1.1 Low-dose aspirin. Aspirin acts via irreversible inhibition of pla-

telet cyclooxygenase-1 and thus thromboxane production, which is

normally complete with chronic dosing >_75 mg/day. The gastrointes-

tinal side effects of aspirin increase at higher doses, and current evi-

dence supports a daily dose of 75 100 mg for the prevention of

ischaemic events in CAD patients with or without a history of

MI.

268270

As cyclooxygenase-1 inhibition by aspirin is consistent and

predictable in adherent patients, no platelet function testing is

required to monitor individual response.

271

Although other non-

selective non-steroidal anti-inflammatory drugs, such as ibuprofen,

reversibly inhibit cyclooxygenase-1, their adverse effects on cardio-

vascular risk indicate that they cannot be recommended as an alter-

native treatment in patients with aspirin intolerance.

272

3.3.2.1.2 Oral P2Y

inhibitors. P2Y

inhibitors block the platelet P2Y

receptor, which plays a key role in platelet activation and the amplifi-

cation of arterial thrombus formation. Clopidogrel and prasugrel are

thienopyridine prodrugs that irreversibly block P2Y

via active

metabolites. Ticagrelor is a reversibly-binding P2Y

inhibitor that

does not require metabolic activation.

The CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of

Ischaemic Events) trial showed an overall slight benefit of clopidogrel

compared with aspirin, with a similar safety profile, in preventing car-

diovascular events in patients with previous MI, previous stroke, or

PAD.

273

Subgroup analysis suggested greater benefit of clopidogrel in

patients with PAD. Despite its lesser antiplatelet efficacy, clopidogrel

demonstrated equivalent efficacy to ticagrelor in patients with

PAD.

274

Clopidogrel is limited by variable pharmacodynamic effects

related to variable efficiency of conversion to its active metabolite,

partly associated with loss-of-function variants in the CYP2C19 gene,

leading to a lack of efficacy in some patients.

271

Drugs that inhibit

CYP2C19, such as omeprazole, may reduce the response to

clopidogrel.

275

Prasugrel has more rapid, more predictable, and, on average,

greater antiplatelet effect compared with clopidogrel, and is not sus-

ceptible to drug interactions or the effect of CYP2C19 loss-of-

function variants. Prasugrel has greater efficacy than clopidogrel in

aspirin-treated patients with ACS undergoing PCI, but not in medically-

managed patients with ACS.

276, 277

Prasugrel has been associated with

more non-fatal and fatal bleeding events than clopidogrel in ACS

patients undergoing PCI, leading to apparent harm in those with a his-

tory of ischaemic stroke, and a lack of apparent benefit in those aged

>75 years or with body weight <60 kg.

276

Ticagrelor has the most predictable and consistently high level of

P2Y

inhibition during maintenance therapy in adherent patients,

219

and also has more rapid onset, as well as more rapid and predictable

offset of action compared with clopidogrel.

278280

Ticagrelor as

monotherapy appears to have similar efficacy and safety to aspirin

monotherapy in patients with previous PCI.

281

Ticagrelor, with a 180

mg loading dose followed by 90 mg b.i.d., achieved greater reduction

of ischaemic events compared with clopidogrel in aspirin-treated

ACS patients, regardless of revascularization strategy, at the expense

of more non-fatal bleeding.

282,283

Ticagrelor at doses of 90 or 60 mg

b.i.d. reduced the 3 year combined incidence of MI, stroke, or cardio-

vascular death compared with placebo in stable aspirin-treated

patients with a history of MI 1 3yearspreviously.

284

Both ticagrelor

doses increased non-fatal but not fatal bleeding. The equivalent effica-

cies and similar safeties of the two ticagrelor doses were explained

by similar levels of platelet inhibition.

285

Ticagrelor may cause dysp-

noea, which is often transient and most often mild and tolerable, but

occasionally necessitates switching to a thienopyridine.

286,287

Ticagrelor is metabolized via CYP3A , and consequently should not be

used with strong CYP3A inhibitors or inducers.

The optimal timing of initiation of P2Y

inhibition before coronary

angiography and possible PCI in patients with CCS is uncertain, but

increasing use of a radial artery approach and clinical experience has

allowed consideration of clopidogrel pre-treatment in patients who

have a high chance of requiring PCI.

284

Limited pharmacodynamic

studies support the unlicensed use of prasugrel or ticagrelor in stable

patients undergoing elective PCI who have a high risk of stent throm-

bosis, but the safety/efficacy balance of this approach, compared with

clopidogrel, has not been established.

288

3.3.2.1.3 Duration of dual antiplatelet therapy. After PCI for stable

angina, 6 months of DAPT achieves the optimum balance of efficacy

and safety in most patients.

284

Premature discontinuation of a P2Y

inhibitor is associated with an increased risk of stent thrombosis and

is discouraged.

284

However, a shorter duration of DAPT may be con-

sidered in those at high risk of life-threatening bleeding in view of the

very low risk of stent thrombosis after 1 3months.

284

On the basis

of phase III trials, 12 months is the recommended default duration of

DAPT after ACS, but shorter duration may again be considered in

those at high bleeding risk.

11,284

A DAPT study of patients undergoing

PCI showed that extended therapy beyond 12 months with clopidog-

rel or prasugrel reduced ischaemic events and stent thrombosis, but

without mortality benefit and at the expense of increased bleeding.

289

A greater benefit of extended clopidogrel or prasugrel was seen in

patients who were treated for MI.

290

The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in

Patients with Prior Heart Attack Using Ticagrelor Compared to

Placebo on a Background of Aspirin Thrombolysis In Myocardial

Infarction 54) trial demonstrated that long-term therapy with ticagre-

lor 60 or 90 mg b.i.d., commenced in stable patients >_1 year after MI,

reduced ischaemic events at the expense of more non-fatal bleed-

ing.

284

The 60 mg dose appeared better tolerated and is approved in

many countries for this indication. Subgroup analysis demonstrated

greater absolute reductions in ischaemic events with long-term tica-

grelor (60 mg b.i.d.) in higher-risk post-MI patients with diabetes,

PAD, or multivessel CAD.

291 293

3.3.2.2 Anticoagulant drugs in sinus rhythm

Anticoagulant drugs inhibit the action and/or formation of thrombin,

which plays a pivotal role in both coagulation and platelet activation.

Consequently, anticoagulants have been shown to reduce the risk of

arterial thrombotic events. The superior efficacy and safety of DAPT,

30 ESC Guidelines

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compared with aspirin and anticoagulation, in preventing stent

thrombosis led to the latter strategy being abandoned in favour of

DAPT following PCI.

284

Combination of antiplatelet therapy and

standard anticoagulant doses of warfarin or apixaban for secondary

prevention after ACS was associated with an unfavourable balance of

efficacy and bleeding.

294,295

However, recently reported studies have

renewed interest in combining lower anticoagulant doses with anti-

platelet therapy.

3.3.2.2.1 Low-dose rivaroxaban. Rivaroxaban is a factor Xa inhibitor

that has been studied at a low dose of 2.5 mg b.i.d. in several popula-

tions of patients in sinus rhythm, this dose being one-quarter of the

standard dose used for anticoagulation in patients with AF.

Rivaroxaban 2.5 mg b.i.d., compared with placebo, reduced the com-

posite of MI, stroke, or cardiovascular death in stabilized patients

treated predominantly with aspirin and clopidogrel following ACS, at

the expense of increased bleeding but with evidence of a reduction in

cardiovascular death.

296

Subsequently, in the COMPASS

(Cardiovascular Outcomes for People Using Anticoagulation

Strategies) trial, the same regimen in combination with aspirin was

compared with aspirin alone, as well as rivaroxaban 5 mg b.i.d. alone,

in patients with CCS or PAD, and showed reduced ischaemic events

at the expense of increased risk of predominantly non-fatal bleed-

ing.

297

Of note, the pre-specified significance thresholds for cardio-

vascular mortality and all-cause mortality were not met. Greater

absolute risk reductions were seen in higher-risk patients with diabe-

tes, PAD, or moderate chronic kidney disease (CKD), as well as cur-

rent smokers. In GEMINI-ACS (A Study to Compare the Safety of

Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either

Clopidogrel or Ticagrelor Therapy in Participants With Acute

Coronary Syndrome), rivaroxaban 2.5 mg b.i.d. was compared with

aspirin in patients treated with a P2Y

inhibitor who were stable fol-

lowing PCI. The results suggested similar safety of rivaroxaban to

aspirin in this setting, but larger studies are required to substantiate

this finding.

298

In addition, the safety of performing PCI without

aspirin pre-treatment is unknown.

3.3.2.3 Anticoagulant drugs in atrial fibrillation

Anticoagulant therapy is recommended in patients with AF and CCS

for reduction of ischaemic stroke and other ischaemic events.

Anticoagulants in AF patients have demonstrated superiority over

aspirin monotherapy or clopidogrel-based DAPT for stroke preven-

tion, and are therefore recommended for this indication.

299

When

oral anticoagulation is initiated in a patient with AF who is eligible for

a non-vitamin K antagonist oral anticoagulant (NOAC; apixaban,

dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in

preference to a vitamin K antagonist (VKA).

299

3.3.2.3.1 Combination anticoagulant and antiplatelet therapy following per-

cutaneous coronary intervention for patients with atrial fibrillation or

another indication for oral anticoagulation. No studies to date have spe-

cifically focused on CCS patients with AF undergoing PCI and clinical

decisions must be based on clinical trials that have included a large

proportion of patients with ACS. For peri-procedural management,

it is recommended that interruption of VKA is avoided, if feasible,

whereas it is recommended that NOAC therapy is stopped for

12 48 h before elective PCI, depending on renal function and the

particular NOAC regimen.

300

Radial artery access is preferred along

with intraprocedural unfractionated heparin either at a standard dose

(70 100 U/kg) or, in those with uninterrupted VKA, at a lower dose

of 3050 U/kg.

300

Pre-treatment with aspirin 75 100 mg daily is rec-

ommended, and clopidogrel (300 600 mg loading dose if not on

long-term maintenance therapy) is recommended in preference to

prasugrel or ticagrelor.

300

VKA-treated patients receiving aspirin and

clopidogrel post-PCI should have a target international normalized

ratio in the range of 2.0 2.5, aiming for high time in therapeutic range

(>70%).

300

Subsequent to post-PCI trials of different antithrombotic

regimens considered in previous Guidelines,

88,284

the AUGUSTUS

trial (An Open-label, 2  2 Factorial, Randomized Controlled,

Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K

Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial

Fibrillation and Acute Coronary Syndrome or Percutaneous

Coronary Intervention) showed, firstly, that apixaban 5 mg b.i.d. (i.e.

the licensed dose for thromboprophylaxis in AF) was associated with

significantly less major or clinically relevant non-major bleeding than

VKA; and, secondly, that aspirin, compared with placebo, was associ-

ated with significantly more bleeding, with the safest combination

being apixaban and placebo in addition to P2Y

inhibitor (predomi-

nantly clopidogrel).

301

However, there were numerically, but not

statistically significantly, more stent thrombosis events with placebo

than with aspirin, and the trial was not powered to assess differences

in these events between groups.

301

Consequently, when concerns

about thrombotic risk prevail over concerns about bleeding risk, >_1

month of triple therapy [oral anticoagulant (OAC), aspirin, and clopi-

dogrel] is recommended to cover the period when the risk of stent

thrombosis is presumed to exceed the risk of bleeding.

300,301

There

is currently limited evidence to support the use of OACs with tica-

grelor or prasugrel as dual therapy after PCI as an alternative to triple

therapy.

300,301

3.3.2.3.2 Long-term combination therapy in patients with atrial fibrillation

or another indication for anticoagulation. OAC monotherapy is gener-

ally recommended 6 12 months after PCI in patients with AF, as

there is a lack of specific data supporting long-term treatment with an

OAC and a single antiplatelet agent; however, in highly selected cases

with high ischaemic risk, dual therapy with anOAC and aspirin or clo-

pidogrel may be considered.

300

3.3.2.4 Proton pump inhibitors

Proton pump inhibitors reduce the risk of gastrointestinal bleeding in

patients treated with antiplatelet drugs and may be a useful adjunctive

treatment for improving safety.

275

Long-term proton pump inhibitor

use is associated with hypomagnesaemia, but the role of monitoring

serum magnesium levels is uncertain. Proton pump inhibitors that

inhibit CYP2C19, particularly omeprazole and esomeprazole, may

reduce the pharmacodynamic response to clopidogrel. Although this

has not been shown to affect the risk of ischaemic events or stent

thrombosis, co-administration of omeprazole or esomeprazole with

clopidogrel is generally not recommended.

3.3.2.5 Cardiac surgery and antithrombotic therapy

Aspirin should normally be continued in patients with CCS under-

going elective cardiac surgery, and other antithrombotic drugs

stopped at intervals according to their duration of action and

ESC Guidelines 31

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indication (prasugrel stopped >_7 days before; clopidogrel >_5 days

before; ticagrelor >_3 days before; and rivaroxaban, apixaban, edoxa-

ban, and dabigatran 1 2 days before depending on dose and renal

function). Reloading of aspirin after CABG surgery may improve graft

patency.

302

The role of DAPT or dual therapy with aspirin and rivar-

oxaban after CABG surgery is uncertain as large prospective studies

are lacking. However, RCT results have suggested higher graft

patency rates with DAPT compared with aspirin

monotherapy.

284, 303 ,304

3.3.2.6 Non-cardiac surgery and antithrombotic therapy

Non-cardiac surgery is associated with an increased risk of MI.

Following PCI, whenever possible, it is recommended to postpone

elective surgery until the recommended course of DAPT has been

completed. Usually, this will mean delaying surgery until 6 months

after PCI, but surgery between 3 6 months may be considered by

a multidisciplinary team, including an interventional cardiologist, if

clinically indicated. In most types of surgery, aspirin should be con-

tinued as the benefit outweighs the bleeding risk, but this may not

be appropriate for procedures associated with extremely high

bleeding risk (intracranial procedures, transurethral prostatectomy,

intraocular procedures, etc.).

284

The COMPASS study included

CCS patients with a history of peripheral revascularization proce-

dures, and demonstrated benefits of aspirin and rivaroxaban 2.5 mg

b.i.d. compared with aspirin alone, including reductions in major

adverse limb events and mortality, suggesting the need to risk-

stratify patients after non-cardiac vascular surgery for atheroscler-

otic disease.

305,306

Recommendations for event prevention I

Recommendations Class

Level

Antithrombotic therapy in patients with CCS and in sinus rhythm

Aspirin 75 100 mg daily is recommended in patients with a previous MI or revascularization.

270

Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance.

273

Clopidogrel 75 mg daily may be considered in preference to aspirin in symptomatic or asymptomatic patients, with either

PAD or a history of ischaemic stroke or transient ischaemic attack.

273

IIb B

Aspirin 75 100 mg daily may be considered in patients without a history of MI or revascularization, but with deﬁnitive evi-

dence of CAD on imaging. IIb C

Adding a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with

ahigh risk of ischaemic events

and without high bleeding risk

(see Table 9 for options).

289,296,297,307

IIa A

Adding a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at

least a moderately increased risk of ischaemic events

and without high bleeding risk

(see Table 9 for

options).

289,296,297,307

IIb A

Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm

Aspirin 75 100 mg daily is recommended following stenting.

284

Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) is recommended,

in addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (13

months) is indicated due to risk or the occurrence of life-threatening bleeding.

284

Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) should be consid-

ered for 3 months in patients with a higher risk of life-threatening bleeding.

284

IIa A

Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) may be considered

for 1 month in patients with very high risk of life-threatening bleeding.

284

IIb C

Prasugrel or ticagrelor may be considered, at least as initial therapy, in speciﬁc high-risk situations of elective stenting (e.g.

suboptimal stent deployment or other procedural characteristics associated with high risk of stent thrombosis, complex

left main stem, or multivessel stenting) or if DAPT cannot be used because of aspirin intolerance.

IIb C

Antithrombotic therapy in patients with CCS and AF

When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC,

a NOAC is recommended in pref-

erence to a VKA.

299301,308311

Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and

a CHA

-VASc score

>_2 in males and >_3 in females.

299

Continued

32 ESC Guidelines

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Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF

and a CHA

-VASc score

of 1 in males and 2 in females.

299

IIa B

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 risk of recurrent ischaemic events

who do not have a high bleeding risk.

d 295,297 , 299

IIb B

Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC

It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent

implantation. IC

In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d.,

edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.)

is used in preference to a VKA in combination with antiplatelet

therapy.

300,301,308,310,311

When rivaroxaban is used and concerns about high bleeding risk

prevail over concerns about stent thrombosis

ischaemic stroke,

rivaroxaban 15 mg o.d. should be considered in preference to rivaroxaban 20 mg o.d. for the duration

of concomitant single or dual antiplatelet therapy.

300,301,308,310

IIa B

When dabigatran is used and concerns about high bleeding risk

prevail over concerns about stent thrombosis

or ischae-

mic stroke,

dabigatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for the duration of

concomitant single or dual antiplatelet therapy.

300,301,308

IIa B

After uncomplicated PCI, early cessation (<_1 week) of aspirin and continuation of dual therapy with an OAC and clopi-

dogrel should be considered if the risk of stent thrombosis

is low, or if concerns about bleeding risk prevail over con-

cerns about the risk of stent thrombosis,

irrespective of the type of stent used.

301,308310

IIa B

Triple therapy with aspirin, clopidogrel, and an OAC for >_1 month should be considered when the risk of stent throm-

bosis

outweighs the bleeding risk, with the total duration (<_6 months) decided according to assessment of these risks

and clearly speciﬁed at hospital discharge.

IIa C

In patients with an indication for a VKA in combination with aspirin and/or clopidogrel, the dose intensity of the VKA

should be carefully regulated with a target international normalized ratio in the range of 2.0 2.5 and with time in thera-

peutic range >70%.

300,301,308310

IIa B

Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with

an OAC, aspirin, and clopidogrel in patients with a moderate or high risk of stent thrombosis,

irrespective of the type of

stent used.

IIb C

The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C

Use of proton pump inhibitors

Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC

monotherapy who are at high risk of gastrointestinal bleeding.

284

AF = atrial ﬁbrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA

-VASc = Cardiac failure, Hypertension,

Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 65 74 and Sex category [Female]; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy;

eGFR = estimated glomerular ﬁltration rate; HF = heart failure; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant;

o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.

Class of recommendation.

Level of evidence.

Diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 15 59 mL/min/1.73 m

Prior history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointes-

tinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal fail-

ure requiring dialysis or with eGFR <15 mL/min/1.73 m

At least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 15 59 mL/min/1.73 m

See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >75 80 years, and/or drug

interactions.

Congestive HF, hypertension, age >_75 years (2 points), diabetes, prior stroke/transient ischaemic attack/embolus (2 points), vascular disease (CAD on imaging or angiogra-

phy,

312

prior MI, PAD, or aortic plaque), age 65 74 years, and female sex.

Risk of stent thrombosis encompasses (i) the risk of thrombosis occurring and (ii) the risk of death should stent thrombosis occur, both of which relate to anatomical, proce-

dural, and clinical characteristics. Risk factors for CCS patients include stenting of left main stem, proximal LAD, or last remaining patent artery; suboptimal stent deployment;

stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antith-

rombotic therapy.

ESC Guidelines 33

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3.3.3 Statins and other lipid-lowering drugs

Dyslipidaemia should be managed according to lipid guidelines with

pharmacological and lifestyle intervention.

315

Patients with estab-

lished CAD are regarded as being at very high risk for cardiovascular

events and statin treatment must be considered, irrespective of LDL-

C levels. The goal of treatment is to lower LDL-C to <1.8 mmol/L

(<70 mg/dL) or at least to reduce it by 50% if the baseline LDL-C

level is 1.8 3.5 mmol/L (70 135 mg/dL). When this level cannot be

achieved, the addition of ezetimibe has been demonstrated to

decrease cholesterol and cardiovascular events in post-ACS patients,

and in those with diabetes,

316

with no further effect on mortality.

317

In addition to exercise, diet, and weight control, which should be rec-

ommended to all patients, dietary supplements including phytosterols

may lower LDL-C to a lesser extent, but have not been shown to

improve clinical outcomes.

318

These are also used in patients with

intolerance to statins who constitute a group at higher risk for cardio-

vascular events.

319

Trials published since 2015 have demonstrated

that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors

(evolocumab

320

and alirocumab

321323

) are very effective at reducing

cholesterol, lowering LDL-C in a stable fashion to <_1.3 mmol/L (50

mg/dL). In outcomes trials, these agents have demonstrated a reduc-

tion of cardiovascular and mainly ischaemic events, with little or no

impact on mortality.

324

Very low levels of cholesterol are well toler-

ated and associated with fewer events,

325

but the high cost of PCSK9

inhibitors, unaffordable for many health systems,

326

and their

unknown long-term safety have limited their use to date. Low-

density lipoprotein apheresis and new therapies such as mipomersen

and lomitapide need further research.

For patients undergoing PCI, high-dose atorvastatin has been

shown to reduce the frequency of peri-procedural eventsin both sta-

tin-naı ¨ve patients and patients receivingchronic statin therapy.

327

3.3.4 Reninangiotensinaldosterone system blockers

ACE inhibitors can reduce mortality, MI, stroke, and HF

among patients with LV dysfunction,

328 330

previous vascular

disease,

331 333

and high-risk diabetes.

334

It is recommended

that ACE inhibitors [or angiotensin receptor blockers (ARBs) in

cases of intolerance] be considered for the treatment of

patients with CCS with coexisting hypertension, LVEF <_40%, dia-

betes, or CKD, unless contraindicated (e.g. severe renal impair-

ment, hyperkalaemia, etc.). However, not all trials have

demonstrated that ACE inhibitors reduce all-cause death, cardio-

vascular death, non-fatal MI, stroke, or HF in patients with athero-

sclerosis and without impaired LV function.

331, 332,335

A meta-

analysis, including 24 trials and 61 961 patients, documented that,

in CCS patients without HF, renin-angiotensin system (RAS) inhibi-

tors reduced cardiovascular events and death only when compared

with placebo, but not when compared with active controls.

336

Hence, ACE inhibitor therapy in CCS patients without HF or high

cardiovascular risk is not generally recommended, unless required

to meet BP targets.

Neprilysin is an endogenous enzyme that degrades vasoactive pep-

tides such as bradykinin and natriuretic peptides. Pharmacological

inhibition of neprilysin raises the levels of these peptides, enhancing

diuresis, natriuresis, myocardial relaxation, and antiremodelling, and

reducing renin and aldosterone secretion. The first in class is

LCZ696, which combines valsartan and sacubitril (neprilysin inhibi-

tor) in a single pill. In patients with HF (LVEF <_35%) who remain

symptomatic despite optimal treatment with an ACE inhibitor, a

beta-blocker, and a mineralocorticoid receptor antagonist (MRA),

sacubitril/valsartan is recommended as a replacement for an ACE

inhibitor to further reduce the risk of HF hospitalization and death in

ambulatory patients.

337

Aldosterone blockade with spironolactone or eplerenone is rec-

ommended for use in post-MI patients who are already receiving

therapeutic doses of an ACE inhibitor and a beta-blocker, have an

LVEF < _35%, and have either diabetes or HF.

338,339

Caution should be

exercised when MRAs are used in patients with impaired renal func-

tion [estimated GFR (eGFR) <45 mL/min/1.73 m

] and in those with

serum potassium levels > _5.0 mmol/L.

340

Table 9 Treatment options for dual antithrombotic therapy in combination with aspirin 75 2 100 mg daily in patients

who have a high

or moderate

risk of ischaemic events, and do not have a high bleeding risk

Drug option Dose Indication Additional cautions References

Clopidogrel 75 mg o.d. Post-MI in patients who have tolerated DAPT for 1 year

289,290

Prasugrel 10 mg o.d or 5 mg o.d.; if body

weight <60 kg or age >75 years

Post-PCI for MI in patients who have tolerated

DAPT for 1 year

Age >75 years

289,290,313

Rivaroxaban 2.5 mg b.i.d. Post-MI >1 year or multivessel CAD Creatinine clearance

15 - 29 mL/min

297

Ticagrelor 60 mg b.i.d. Post-MI in patients who have tolerated DAPT for 1 year

291293,307,314

Treatment options are presented in alphabetical order.

b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular ﬁltration rate;

HF = heart failure; MI = myocardial infarction; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneo us coronary intervention.

High risk of ischaemic events is deﬁned as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with

eGFR 15 - 59 mL/min/1.73 m

Moderately increased risk of ischaemic events is deﬁned as at least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD,

HF, or CKD with eGFR 15 -59 mL/min/1.73 m

High bleeding risk is deﬁned as history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia

due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old

age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m

34 ESC Guidelines

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3.3.5 Hormone replacement therapy

The results from large randomized trials have shown that hormone

replacement therapy provides no prognostic benefit and increases

the risk of CVDin women aged >60 years.

344

3.4 Revascularization

In patients with CCS, optimal medical therapy is key for reducing

symptoms, halting the progression of atherosclerosis, and preventing

atherothrombotic events. Myocardial revascularization plays a cen-

tral role in the management of CCS on top of medical treatment, but

always as an adjunct to medical therapy without supplanting it. The

two objectives of revascularization are symptom relief in patients

with angina and/or improvement of prognosis.

Previous Guidelines support indications for revascularization

mainly in patients with CCS who receive Guideline-recommended

optimal medical therapy and continue to be symptomatic, and/or in

whom revascularization may ameliorate prognosis.

These recom-

mendations suggested that revascularization in patients with angina

and significant stenosis was often a second-line therapy after medical

therapy had been unsuccessful. However, angina is associated with

impaired quality of life, reduced physical endurance, mental depres-

sion, and recurrent hospitalizations and office visits, with impaired

clinical outcomes.

345,346

Revascularization by PCI or CABG may effectively relieve angina,

reduce the use of antianginal drugs, and improve exercise capacity

and quality of life compared with a strategy of medical therapy

alone. In the 5 year follow-up of the FAME 2 (Fractional Flow

Reserve versus Angiography for Multivessel Evaluation 2) trial, revas-

cularization improved quality of life, and reduced the use of antiangi-

nal drugs and associated side effects.

347

The ORBITA (Objective

Randomised Blinded Investigation with optimal medical Therapy or

Angioplasty in stable angina) study, entailing a sham procedure in the

control group, found no significant improvement in exercise capacity

with PCI.

262

The study highlights a significant placebo component to

the clinical effects, and alerts us to the pitfalls of interpreting end-

points subject to bias in the absence of sham control and blinding.

However, the ORBITA results cannot inform Guidelines due to the

limited trial size, short-term observation time until crossover, and

insufficient power to assess clinical endpoints.

Revascularization by either PCI or CABG also aims to effectively

eliminate myocardial ischaemia and its adverse clinical manifestations

among patients with significant coronary stenosis, and to reduce the

risk of major acute cardiovascular events including MI and cardiovas-

cular death. Numerous meta-analyses comparing a strategy of PCI

with initial medical therapy among patients with CCS have found

348,349

or a modest

104,350,351

benefit, in terms of survival or MI for

an invasive strategy. In this regard, previous Guidelines identified spe-

cific subgroups of patients (based on the anatomy of the coronary

tree, LV function, risk factors, etc.) in whom revascularization may

improve prognosis, indicating that in other groups it may not.

A meta-analysis by Windecker et al. reported an incremental

reduction of death and MI by revascularization vs. medical therapy

only in CCS patients when revascularization was performed with

CABG or new-generation drug-eluting stents (DES), as opposed to

balloon angioplasty, bare-metal stents, or early DES.

351

Data

reported in 2018 indicate a potentially broader prognostic impact of

revascularization strategies. The 5 year follow-up of the FAME 2 trial

confirmed a sustained clinicalbenefitin patients treated with PCI spe-

cifically targeting the ischaemia-producing stenoses (i.e. FFR <0.80)

plus optimal medical therapy vs. optimal medical therapy alone in

terms of a significantly lower rate of urgent revascularization (hazard

ratio 0.27, 95% CI 0.18 0.41), and a lower rate of spontaneous MI

(hazard ratio 0.62, 95% CI 0.39 0.99).

347

In contrast to some of the

earlier meta-analyses, this signal was confirmed in a patient-level

meta-analysis including 2400 subjects, all of whom underwent inva-

sive physiological guidance, showing a significant reduction in cardiac

death and MI after a median follow-up of 33 months with FFR-guided

Recommendations for event prevention II

Lipid-lowering drugs Class

Level

Statins are recommended in all patients with CCS.

c341,342

If a patient's goal

is not achieved with the maximum tolerated dose of statin, combination with ezetimibe is

recommended.

317,320

For patients at very high risk who do not achieve their goal

on a maximum tolerated dose of statin and ezetimibe,

combination with a PCSK9 inhibitor is recommended.

320,323

ACE inhibitors

ACE inhibitors (or ARBs) are recommended if a patient has other conditions (e.g. heart failure, hypertension, or

diabetes).

328330

ACE inhibitors should be considered in CCS patients at very high risk of cardiovascular events.

331,332,335,336

IIa A

Other drugs

Beta-blockers are recommended in patients with LV dysfunction or systolic HF.

211,212,214

In patients with a previous STEMI, long-term oral treatment with a beta-blocker should be considered.

213,220222,225,343

IIa B

ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CCS = chronic coronary syndrome; HF = heart failure; LV = left ventricular; PCSK9 = proprotein

convertase subtilisin-kexin type 9; STEMI = ST-elevation myocardial infarction.

Class of recommendation.

Level of evidence.

The treatment goals are shown in the European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias.

315

ESC Guidelines 35

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PCI vs. medical therapy (hazard ratio 0.74, 95% CI 0.56 0.989;

P=0.041).

352

Together, these new data support a less restrictive indi-

cation for revascularization in CCS, in addition to specific anatomy

[e.g. left main (LM)] or extended ischaemia (>10%), when PCI is

restricted to angiographic stenoses on large vessels causing a signifi-

cant intracoronary pressure gradient. Figure 9 summarizes a practical

approach to the indications of revascularization in CCS according to

the presence or absence of symptoms, and documentation of non-

invasive ischaemia. However, the individual risk-benefit ratio should

always be evaluated and revascularization considered only if its

expected benefit outweighs its potential risk. Also, the aspect of

shared decision-making is key, with full information given to the

patient about the anticipated advantages and disadvantages of the

two strategies, including the DAPT-related bleeding risks in cases of

revascularization by PCI. For the discussion of the best choice

between revascularization modalities PCI or CABG  for individual

patients, we refer readers to the 2018 ESC myocardial revasculariza-

tion Guidelines.

4 Patients with new onset of heart

failure or reduced left ventricular

function

CAD is the most common cause of HF in Europe, and most of the

trial evidence supporting management recommendations is based on

©ESC 2019

No Yes

Yes No

Yes

Diameter stenosis

>90%

FFR ≤0.80 or iwFR

≤0.89 in major

vessel

LVEF ≤35% due

to CAD

Large area

of ischaemia

(>10% of LV)

Diameter stenosis

>90%

FFR ≤0.80 or iwFR

≤0.89 in major

vessel

LVEF ≤ 35% due

to CAD

Identify lesions with

FFR ≤0.80 or

iwFR ≤0.89

•

Consider revascularization on top of medical therapy

MVD

Documented

ischaemia

Documented

ischaemia

Angina symptoms

Figure 9 Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention

or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or

absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prog-

nostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD

= coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio;LV = left ventricle; LVEF = left ventricular ejection fraction;

MVD = multivessel disease.

36 ESC Guidelines

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research conducted in patients with ischaemic cardiomyopathy. The

pathophysiology results in systolic dysfunction due to myocardial

injury and ischaemia, and most patients with symptomatic HF have

reduced ejection fraction (<40%), although patients with CCS

may also have symptomatic HF and a preserved ejection fraction

(>_50%). Patients with symptomatic HF should be managed clinically

according to the 2016 ESC heart failure Guidelines.

340

History should include the assessment of symptoms suggestive of

HF, especially exercise intolerance and dyspnoea on exertion. All

major past events related to CAD including MI and revascularization

procedures are recorded, as well as all major cardiovascular comor-

bidity requiring treatment such as AF, hypertension, or valvular dys-

function, and non-cardiovascular comorbidity such as CKD, diabetes,

anaemia, or cancer. Current medical therapy, adherence, and toler-

ance should be reviewed.

Physical examination should assess the nutritional status of patients,

and estimate biological age and cognitive ability. Recorded physical

signs include heart rate, heart rhythm, supine BP, murmurs suggestive

of aortic stenosis or mitral insufficiency, signs of pulmonary conges-

tion with basal rales or pleural effusion, signs of systemic congestion

with dependant oedema, hepatomegaly, and elevated jugular venous

pressure.

Aroutine ECG provides information on heart rate and rhythm,

extrasystole, signs of ischaemia, pathological Q waves, hypertrophy,

conduction abnormalities, and bundle branch block.

Imaging should include an echocardiographic examination with

Doppler to evaluate evidence of ischaemic cardiomyopathy with HF

with reduced ejection fraction, HF with mid-range ejection fraction,

or HF with preserved ejection fraction, focal/diffuse LV or right ven-

tricular systolic dysfunction, evidence of diastolic dysfunction, hyper-

trophy, chamber volumes, valvular function, and evidence of

pulmonary hypertension. Chest X-ray can detect signs of pulmonary

congestion, interstitial oedema, infiltration, or pleural effusion. If not

known, coronary angiography (or coronary CTA) should be

performed to establish the presence and extent of CAD, and evalu-

ate the potential for revascularization.

52,53

Laboratory investigations should measure natriuretic peptide levels to

rule-out the diagnosis of suspected HF. When present, the severity of

HF can be assessed.

25,49

Renal function along with serum electrolytes

should be measured routinely to detect the development of renal

insufficiency, hyponatraemia, or hyperkalaemia, especially at the initia-

tion and during up-titration of pharmacological therapy.

The management of patients with symptomatic HF requires

adequate diuretic therapy, preferably with a loop diuretic, to relieve

signs and symptoms of pulmonary and systemic congestion.

Inhibitors of both the RAS system (ACE inhibitors, ARBs, angiotensin

receptor-neprilysin inhibitor) and the adrenergic nervous system

(beta-blockers) are indicated in all symptomatic patients with HF.

340

In patients with persistent symptoms, an MRA is also indicated. Up-

titration of these drugs should be gradual to avoid symptomatic sys-

tolic hypotension, renal insufficiency, or hyperkalaemia.

Patients who remain symptomatic, with LV systolic dysfunction

and evidence of ventricular dysrhythmia or bundle branch block, may

be eligible for a device [cardiac resynchronization therapy (CRT)/

implantable cardioverter-defibrillator]. Such devices may provide

symptomatic relief, reduce morbidity, and improve survival.

353 356

Patients with HF may decompensate rapidly following the onset of

atrial or ventricular dysrhythmia, and should be treated according to

current Guidelines. Patients with HF, and haemodynamically signifi-

cant aortic stenosis or mitral insufficiency, may require percutaneous

or surgical intervention.

Myocardial revascularization should be considered in eligible

patients with HF based on their symptoms, coronary anatomy, and

risk profile. Successful revascularization in patients with HF due to

ischaemic cardiomyopathy may improve LV dysfunction and progno-

sis by reducing ischaemia to viable, hibernating myocardium. If avail-

able, cooperation with a multidisciplinary HF team is strongly

advised.

348,357,358

General recommendations for the management of patients with chronic coronary syndromes and symptomatic heart

failure due to ischaemic cardiomyopathy and left ventricular systolic dysfunction

Recommendations for drug therapy Class

Level

Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF

symptoms.

359,360

Beta-blockers are recommended as essential components of treatment due to their efﬁcacy in both relieving angina, and

reducing morbidity and mortality in HF.

214,361367

ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to

improve symptoms and reduce morbidity and mortality.

333,368

An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition, or an angiotensin recep-

tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.

337,369

An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and

beta-blocker, to reduce morbidity and mortality.

360,370

A short-acting oral or transcutaneous nitrate should be considered (effective antianginal treatment, safe in HF).

371

IIa A

Ivabradine should be considered in patients with sinus rhythm, an LVEF <_35% and a resting heart rate >70 b.p.m. who

remain symptomatic despite adequate treatment with a beta-blocker, ACE inhibitor, and MRA, to reduce morbidity and

mortality.

238,372,373

IIa B

Amlodipine may be considered for relief of angina in patients with HF who do not tolerate beta-blockers, and is consid-

ered safe in HF.

374,375

IIb B

Continued

ESC Guidelines 37

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5 Patients with a long-standing

diagnosis of chronic coronary

syndromes

In patients with a long-standing diagnosis of CCS, lifelong treatment

and surveillance are required (Figure 10 ). The clinical course of

patients with CCS may be benign over the course of time. However,

patients with CCS may develop a variety of cardiovascular complica-

tions or undergo therapeutic measures, some directly related to the

underlying CAD, and some having therapeutic or prognostic interac-

tions with the underlying disease. Risk for complications may occur in

an otherwise asymptomatic patient, and thus the assessment of risk

status applies to symptomatic and asymptomatic patients.

Periodic assessment of the patient's individual risk may be consid-

ered (Figure 10 ). Scores that apply clinical parameters have been

shown to predict outcomes among patients with CCS. Moreover, if

the clinical parameters are complemented by biomarkers, such a risk

score may be even more accurate. In 2017, a biomarker-based risk

model to predict cardiovascular mortality in patients with CCS was

developed and externally validated.

398

5.1 Patients with stabilized symptoms <1

year after an acute coronary syndrome

or patients with recent revascularization

After revascularization and/or after stabilized ACS (<1 year), patients

should be monitored more vigilantly, because they are at greater risk

for complications and because they are subject to changes in pharma-

cological treatment.

Thus, we recommend at least two visits in the

first year of follow-up. In a patient who had LV systolic dysfunction

before the revascularization procedure or after the ACS, a reassess-

ment of LV function must be considered 8 12 weeks after the inter-

vention. Cardiac function may have improved, owing to mechanisms

such as recovery from myocardial stunning or hibernation, which

may be reversed by revascularization.

52,53

Conversely, cardiac func-

tion may have deteriorated given other concomitant CVD (e.g. valvu-

lar disease, infection or inflammation, arrhythmia, etc.). In such cases,

these other damaging factors need to be identified and treated.

Likewise, non-invasive assessment of myocardial ischaemia may be

considered after revascularization to rule-out residual ischaemia or

to document the residual ischaemia as reference for subsequent

assessments over time.

5.2 Patients > 1 year after initial diagnosis

or revascularization

To assess a patient's risk, an annual evaluation by a cardiovascular

practitioner (cardiologist, general physician, or nurse) is warranted,

even if the patient is asymptomatic. It is recommended that the

annual evaluation should assess the patient's overall clinical status and

medication compliance, as well as the risk profile (as reflected by risk

scores). Laboratory tests—which include a lipid profile, renal func-

tion, a complete blood count, and possibly biomarkers—should be

performed every 2 years.

A patient with a worsening risk score

over time may warrant more intense therapy or diagnostic measures,

although risk score-guided therapy has not yet been proved to ameli-

orate outcomes.

A 12 lead ECG should be a part of every such visit to delineate

heart rate and heart rhythm, to detect changes suggestive of silent

ischaemia/infarction, and to discern abnormalities in the specific elec-

trocardiographic segments (e.g. PR, QRS, and QT intervals). It may

be beneficial to assess LV function (diastolic and systolic), valvular sta-

tus, and cardiac dimensions in apparently asymptomatic patients

every 3 5years.

52,53

In cases of unexplained reduction in systolic LV

function, especially if regional, imaging of coronary artery anatomy is

recommended. Likewise, it may be beneficial to assess non-invasively

for silent ischaemia in an apparently asymptomatic patient every 35

For devices, comorbidities, and revascularization

In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker

rather than right ventricular pacing is recommended.

353

An implantable cardioverter-deﬁbrillator is recommended in patients with documented ventricular dysrhythmia causing

haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF <_35%, to

reduce the risk of sudden death and all-cause mortality.

354,376382

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration >_150 ms and LBBB QRS

morphology, and with LVEF <_35%, despite optimal medical therapy to improve symptoms, and reduce morbidity and

mortality.

355,356,383392

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration 130 - 149 ms and LBBB

QRS morphology, and with LVEF <_35%, despite optimal medical therapy to improve symptoms, and reduce morbidity

and mortality.

355,356,383392

Comprehensive risk proﬁling and multidisciplinary management, including treatment of major comorbidities such as

hypertension, hyperlipidaemia, diabetes, anaemia, and obesity, as well as smoking cessation and lifestyle modiﬁcation, are

recommended.

393396

Myocardial revascularization is recommended when angina persists despite treatment with antianginal drugs.

348,357,397

ACE inhibitor = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; b.p.m. = beats per minute; CCS = chronic coronary syndromes; CRT = cardiac resynch-

ronization therapy; HF = heart failure; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = miner-

alocorticoid receptor antagonist.

Class of recommendation.

Level of evidence.

38 ESC Guidelines

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years, preferably applying stress imaging. Coronary CTA should not

be used for follow-up of patients with established CAD given its

strength on morphological insight, but lack of functional information

related to ischaemia. However, coronary CTA may be used for

unique cases, such as delineation of patency of coronary artery

bypass grafts.

The lipid profile and glycaemia status should be reassessed periodi-

cally to determine efficacy of treatment and, in patients without dia-

betes, to detect new development of diabetes. There is no evidence

to support recommendations for the frequency of reassessment of

these risk factors, butconsensus suggests annual evaluation.

Elevated inflammatory markers, particularly of high-sensitivity C-

reactive protein, have also been associated with an increased event

risk in patients with and without CAD in multiple studies,

although

the robustness of the association has been questioned because of

reporting and publication bias.

399

In addition, von Willebrand factor,

interleukin-6, and N-terminal pro-B-type natriuretic peptide (NT-

proBNP) have identified as been predictors of outcome.

Other

©ESC 2019

cardiologist, internist, general practitioner, or cardiovascular nurse

Invasive coronary

angiography

As necessary, for patients at high risk based on noninvasive ischaemia

testing, or severe angina symptoms (e.g. CCS class 3-4).

Not recommended solely for risk stratification.

Stress test for

inducible ischaemia

As necessary, to investigate changes in symptoms level, and/or early

(e.g. 1-3 months) after revascularization to set as a reference

and/or periodically (e.g. every 3-5 years) to reassess ischaemia.

Echocardiography

at rest

Early (e.g. 1-3 months) after revascularization to set as a reference and/or

periodically (e.g. at 1 year if previously abnormal and/or every 3-5 years) to

evaluate LV function, valvular status and haemodynamic status.

Destabilization Destabilization

Stabilization

Baseline

3 months

6 months

12 months

Time from

initial evaluation

of post-ACS CCS

18 months

24 months

Yea r ly

Post-ACS CCS

(e.g. >1 year after MI)

Yea r ly

Long-standing diagnosis

of CCS (>1 year)

Baseline

3 months

6 months

12 months

Time from

initial evaluation

of recent CCS

Recent CCS diagnosis

or revascularization

Legend

Time for decision-making on

DAPT continuation in PCI patients

Time for decision-making on

optional dual antithrombotic therapy

(see table 9)

Advisable timepoint

Optional timepoint

Cardiovascular

caregiver

visit

Risk score(s)

stratification

Resting

ECG

ACS

Figure 10 Proposed algorithm according to patient types commonly observed at chronic coronary syndrome outpatient clinics. The frequency of fol-

low-up may besubject to variation basedon clinical judgement. ACS = acute coronary syndromes; CCS = chronic coronary syndromes; DAPT = dual anti-

platelet therapy; ECG = electrocardiogram; LV = left ventricular; MI = myocardial infarction; PCI = percutaneous coronary intervention.

Cardiologist,

internist, general practitioner, or cardiovascular nurse.

ESC Guidelines 39

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readily available biomarkers shown to predict prognosis in patients

with CCS include heart rate, haemoglobin, and white cell count.

400

Scores based on aggregated biomarkers may have greater success

than individual biomarkers. A multiple biomarker score combining

high-sensitivity C-reactive protein, heat shock protein 70, and fibrin

degradation products significantly improved C-statistics and the net

reclassification index compared with a basic model using clinical

data.

401

Similar results were reported for a combination of high-

sensitivity cardiac troponin T, NT-proBNP, and LDL-C.

398

In several

studies, genetic risk scores have been shown to improve risk predic-

tion above traditional risk factors in general population samples

402,403

and to predict recurrent events in populations with known

CCS.

404407

Although there is additional prognostic value in using

several individual and aggregated biomarkers, there is currently no

evidence that routine use leads to improved care. Nevertheless,

these measurements may have a role in selected patients (e.g. when

testing for haemostatic abnormalities in those with previous MI with-

out conventional riskfactors or a strong family history of CAD).

Patients with unequivocal symptoms suggestive of ACS should be

expeditiously referred for evaluation, applying current Guidelines for

diagnosis and management. Among patients with more equivocal

symptoms, stress imaging is recommended

408

and, if not available and

the ECG is amenable to identification of ischaemia, exercise stress

electrocardiography can be used as an alternative. In patients with

severe angina and a high-risk clinical profile, direct referral for ICA is

recommended, provided that ad hoc physiological assessment of hae-

modynamic stenosis significance is readily available in the catheteriza-

tion laboratory [e.g. instantaneous wave-free ratio (iwFR) or FFR].

Likewise, ICA is recommended for patients with evidence of signifi-

cant ischaemia obtained by non-invasive testing.

6 Angina without obstructive

disease in the epicardial coronary

arteries

In clinical practice, a marked discrepancy between findings regarding

coronary anatomy, the presence of symptoms, and the results of

non-invasive tests frequently occurs.

These patients deserve atten-

tion, as angina and non-obstructive disease are associated with an

increased risk of adverse clinical events.

Low diagnostic yield of ICA

can be explained by the presence of: (i) stenoses with mild or moder-

ate angiographic severity, or diffuse coronary narrowing, with under-

estimated functional significance identified by ICA; (ii) disorders

affecting the microcirculatory domain that escape the resolution of

angiographic techniques; and (iii) dynamic stenoses of epicardial ves-

sels caused by coronary spasm or intramyocardial bridges that are

not evident during CTA or ICA. Intracoronary pressure measure-

ments are useful in circumventing the first of these scenarios. For

diagnostic workup, patients with angina and/or myocardial ischaemia

showing coronary stenoses with non-ischaemic FFR or iwFR values

may also be labelled as having non-obstructive epicardial disease.

The presence of clear-cut anginal symptoms and abnormal non-

invasive tests in patients with non-obstructed epicardial vessels

should lead to the suspicion of a non-obstructive cause of ischaemia.

Quite often, and mainly as a result of persistence of symptoms,

patients with angina and no obstructive disease undergo multiple

diagnostic tests, including repeated coronary CTA or ICA, that con-

tribute to increased healthcare costs.

409

Because diagnostic pathways

to investigate microcirculatory or vasomotor coronary disorders are

often not implemented, a final diagnosis supported by objective

Recommendations for patients with a long-standing diagnosis of chronic coronary syndromes

Recommendations for asymptomatic patients Class

Level

A periodic visit to a cardiovascular healthcare professional is recommended to reassess any potential change in the risk

status of patients, entailing clinical evaluation of lifestyle-modiﬁcation measures, adherence to targets of cardiovascular

risk factors, and the development of comorbidities that may affect treatments and outcomes.

In patients with mild or no symptoms receiving medical treatment in whom non-invasive risk stratiﬁcation indicates a high

risk, and for whom revascularization is considered for improvement of prognosis, invasive coronary angiography (with

FFR when necessary) is recommended.

Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C

Invasive coronary angiography is not recommended solely for risk stratiﬁcation. III C

Symptomatic patients

Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed

to a reversible cause (e.g. long-standing tachycardia or myocarditis). IC

Risk stratiﬁcation is recommended in patients with new or worsening symptom levels, preferably using stress imaging or,

alternatively, exercise stress ECG.

408

It is recommended to expeditiously refer patients with signiﬁcant worsening of symptoms for evaluation. IC

Invasive coronary angiography (with FFR/iwFR when necessary) is recommended for risk stratiﬁcation in patients with

severe CAD, particularly if the symptoms are refractory to medical treatment or if they have a high-risk clinical proﬁle. IC

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional ﬂow reserve; iwFR = instantaneous wave-free ratio;

LV = left ventricular.

Class of recommendation.

Level of evidence.

40 ESC Guidelines

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evidence is seldom reached. Owing to this, patient dismay and

depression are not rare in this clinical population.

410,411

Of note, the

use of a structured, systematic approach to explore microcirculatory

and vasomotor disorders in patients with non-obstructive CAD, as

delineated below, has been shown to increase diagnostic yield.

412,413

Furthermore, an RCT, which reported in 2018, found that in patients

with non-obstructive coronary disease, tailored treatment guided by

the results of intracoronary testing [coronary flow reserve (CFR),

microcirculatory resistance, and acetylcholine testing] resulted in a

significant reduction of anginal symptoms, compared with conven-

tional, non-guided medical treatment.

414

6.1 Microvascular angina

Patients with microvascular angina typically have exercise-related

angina, evidence of ischaemia in non-invasive tests, and either no

stenoses or mild-to-moderate stenoses (40 60%), revealed by

ICA or CTA, that are deemed functionally non-relevant.

415

Given

the similarity of angina symptoms, a microvascular origin of angina

is typically suspected, after excluding obstructive epicardial coro-

nary stenoses, during diagnostic workup of patients with suspected

myocardial ischaemia. Regional LV wall motion abnormalities rarely

develop during exercise or stress in patients with microvascular

angina.

412,416

Some patients may also have a mixed pattern of

angina, with occasional episodes at rest, particularly associated with

exposure to cold.

Secondary microvascular angina, in the absence of epicardial

obstruction, may result from cardiac or systemic conditions, including

those that cause LV hypertrophy (such as hypertrophic cardiomyop-

athy, aortic stenosis, and hypertensive heart disease) or inflammation

(such as myocarditis or vasculitis).

417

6.1.1 Risk stratification

The presence of microcirculatory dysfunction in patients with CCS

entails a worse prognosis than originally thought, probably because

most recent evidence has been based on follow-up of patients in

whom abnormalities in the microcirculation have been objectively

documented with invasive or non-invasive techniques.

418 423

Microcirculatory dysfunction precedes the development of epicar-

dial lesions, particularly in women,

419

and is associated with impaired

outcomes. Among patients with diabetes undergoing diagnostic

workup, those without obstructive epicardial disease but with an

abnormal CFR have similarly poor long-term prognosis as those with

obstructive epicardial disease.

421

In patients with non-significant cor-

onary stenoses by FFR, the presence of abnormal CFR is associated

with an excess of events in the long-term,

418,422,423

particularly when

the index of microcirculatory resistance(IMR) is also abnormal.

422

6.1.2 Diagnosis

The possibility of a microcirculatory origin of angina should be con-

sidered in patients with clear-cut angina, abnormal non-invasive func-

tional tests, and coronary vessels that are either normal or have mild

stenosis deemed functionally non-significant on ICA or CTA. One of

the challenges in performing a comprehensive assessment of micro-

vascular function is testing the two main mechanisms of dysfunction

separately: impaired microcirculatory conductance and arteriolar

dysregulation.

424426

Yet, outlining which of these two pathways is

affected is critically relevant in setting medical treatment to relieve

patient symptoms.

414

Impaired microcirculatory conductance can be diagnosed by measuring

CFR or minimal microcirculatory resistance (the inverse of conduc-

tance). CFR can be measured non-invasively with transthoracic

Doppler echocardiography [by imaging left anterior descending

(LAD) flow],

427

magnetic resonance imaging (myocardial perfusion

index),

428 430

or PET.

431

Microcirculatory resistance can be measured

in the catheterization laboratory by combining intracoronary pressure

with thermodilution-based data (to calculate the IMR) or Doppler

flow velocity (to calculate hyperaemic microvascular resistance or

HMR).

432,433

Both intracoronary thermodilution and Doppler allow

the calculation of CFR. For decision-making purposes, values of IMR

> _25 units or CFR <2.0 are indicative of abnormal microcirculatory

function.

414

Both CFR and IMR are typically measured while using

intravenous vasodilators, such as adenosine or regadenoson.

In contrast, the diagnosis of arteriolar dysregulation requires the

assessment of endothelial function in the coronary microcirculation

by selective intracoronary acetylcholine infusion (see section 6.5). In

the presence of dysfunctional vascular endothelium or abnormal

function of smooth muscle cells, acetylcholine (an endothelium-

dependent vasodilator that also acts directly on smooth muscle cells)

triggers paradoxical arteriolar vasoconstriction.

434

Thus, in patients

with microvascular angina and arteriolar dysregulation, acetylcholine

challenge is likely to trigger microvascular spasm. This arteriolar

response to acetylcholine causes anginal symptoms with or without

concomitant ischaemic ECG changes, and a decrease in coronary

blood flow velocity if concomitant Doppler measurements are per-

formed. Peripheral pulse tonometry during reactive hyperaemia may

also reveal abnormal systemic endothelial function in patients with

angina and non-obstructive CAD.

435

6.1.3 Treatment

Treatment of microvascular angina should address the dominant

mechanism of microcirculatory dysfunction. In patients with abnor-

mal CFR <2.0 or IMR >_25 units, and a negative acetylcholine provo-

cation test, beta-blockers, ACE inhibitors, and statins, along with

lifestyle changes and weight loss, are indicated.

436,437

Patients devel-

oping ECG changes and angina in response to acetylcholine testing

but without severe epicardial vasoconstriction (all suggestive of

microvascular spasm) may be treated like vasospastic angina patients.

The effectiveness of a tailored treatment strategy was investigated in

the CorMiCa trial, which randomized 151 patients to a stratified

medical treatment (based on the results of CFR, IMR, and acetylcho-

line testing) vs. a standard-care group (including a shaminterventional

diagnostic procedure). At 1 year, there was a significant difference in

angina scores favouring patients assigned to the stratified medical

treatment arm.

414

ESC Guidelines 41

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6.2 Vasospastic angina

Vasospastic angina should be suspected in patients with anginal

symptoms occurring predominantly at rest, with maintained effort

tolerance. The likelihood of vasospastic angina increases when

attacks follow a circadian pattern, with more episodes at night and

in the early morning hours. Patients are frequently younger and

have fewer cardiovascular risk factors than patients with effort

angina, except for cigarette smoking.

442

Coronary vasospasm

should be also suspected in patients with patent coronary stents

and persistent angina.

443,444

6.2.1 Diagnosis

The diagnosis of vasospastic angina is based on detecting transient

ischaemic ST-segment changes during an angina attack (usually at

rest). Patients with Prinzmetal angina represent a special subset in

whom resting angina is accompanied by transient ST-segment eleva-

tion.

442,445

These ECG changes correlate with proximal vessel occlu-

sion and diffuse, distal subocclusive narrowing of epicardial vessels.

As most attacks of vasospastic angina are self-limiting, documentation

of these ECG changes is challenging. Ambulatory ECG monitoring,

preferably with 12 lead recording, may be helpful in patients in whom

vasospastic angina is suspected. The occurrence of ST-segment shifts

at normal heart rate supports the likelihood of myocardial ischaemia

caused by spasm. Extended Holter monitoring (for >1 week) may be

required for successful documentation of transient ST-segment

changes in these patients. Ambulatory ECG monitoring may also be

used to assess the results of medical therapy in controlling the fre-

quency of vasospastic events.

In patients with suspected vasospastic angina and documented ECG

changes, CTA or ICA is indicated to rule-out the presence of fixed

coronary stenosis. Angiographic documentation of coronary spasm

requires the use of a provocation test in the catheterization laboratory.

Given the low sensitivity of hyperventilation and the cold pressor test,

intracoronary administration of acetylcholine or ergonovine during

ICA are the preferred provocation tests.

442

Both pharmacological

agents are safe, provided that they are selectively infused into the left

or right coronary artery, and that triggered spasm is readily controlled

with intracoronary nitrates. A low percentage of patients may develop

ventricular tachycardia/ventricular fibrillation or bradyarrhythmias dur-

ing the provocation test (3.2 and 2.7%, respectively), similar to that

reported during spontaneous spasm attacks (7%).

446

Intravenous

administration of ergonovine for non-invasive tests should be discour-

aged due to the risk of triggering prolonged spasm in multiple vessels,

which may be very difficult to manage and can be fatal.

447

A provocation test for coronary spasm is considered positive when

it triggers: (i) anginal symptoms, (ii) ischaemic ECG changes, and (iii)

severe vasoconstriction of the epicardial vessel. Should the test fail in

triggering all three components, it should be considered equivocal.

442

The development of angina in response to acetylcholine injections in

the absence of angiographically evident spasm, with or without accom-

panying ST-segment changes, may indicate microvascular spasm and is

seen frequently in patients presenting with microvascular angina.

445

6.2.2 Treatment

In patients with epicardial or microcirculatory vasomotor disorders,

CCBs and long-acting nitrates constitute the treatment of choice, in

addition to the control of cardiovascular risk factors and lifestyle

changes.

437,445

Nifedipine has been shown to be effective in reducing

coronary spasm associated with stent implantation.

444

Investigations in patients with suspected coronary micro-

vascular angina

Recommendations Class

Level

Guidewire-based CFR and/or microcirculatory

resistance measurements should be consid-

ered in patients with persistent symptoms, but

coronary arteries that are either angiographi-

cally normal or have moderate stenoses with

preserved iwFR/FFR.

412,413

IIa B

Intracoronary acetylcholine with ECG moni-

toring may be considered during angiography,

if coronary arteries are either angiographically

normal or have moderate stenoses with pre-

served iwFR/FFR, to assess microvascular

vasospasm.

412,438440

IIb B

Transthoracic Doppler of the LAD, CMR, and

PET may be considered for non-invasive

assessment of CFR.

430432,441

IIb B

CFR = coronary ﬂow reserve; CMR = cardiac magnetic resonance; ECG = elec-

trocardiogram; FFR = fractional ﬂow reserve; iwFR = instantaneous wave-free

ratio; LAD = left anterior descending; PET = positron emission tomography.

Class of recommendation.

Level of evidence.

Recommendations for investigations in patients with

suspected vasospastic angina

Recommendations Class

Level

An ECG is recommended during angina if

possible. IC

Invasive angiography or coronary CTA is rec-

ommended in patients with characteristic epi-

sodic resting angina and ST-segment changes,

which resolve with nitrates and/or calcium

antagonists, to determine the extent of under-

lying coronary disease.

Ambulatory ST-segment monitoring should be

considered to identify ST-segment deviation in

the absence of increased heart rate.

IIa C

An intracoronary provocation test should be

considered to identify coronary spasm in

patients with normal ﬁndings or non-obstruc-

tive lesions on coronary arteriography and a

clinical picture of coronary spasm, to diagnose

the site and mode of spasm.

412,414,438440

IIa B

CTA = computed tomography angiography; ECG = electrocardiogram.

Class of recommendation.

Level of evidence.

42 ESC Guidelines

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7 Screening for coronary artery

disease in asymptomatic subjects

In an effort to lower the high burden of coronary deaths in asympto-

matic adults, numerous measurements of risk factors and risk markers,

as well as stress tests, are often performed as screening investigations.

The 2016 European Guidelines on CVD prevention in clinical practice

have focused on these issues in detail.

These recommendations have

been adapted for the purpose of these Guidelines.

In general, the use of risk-estimation systems such as SCORE is

recommended (see also Figure 6 ). Subjects with a family history of

premature CAD should be screened for familial hypercholesterolae-

mia. Coronary calcium score, ankle-brachial index, and carotid ultra-

sound for plaque detection may provide useful information about the

atherosclerotic risk in selected patients, but routine use of bio-

markers or other imaging tests for CAD are not recommended. The

new biomarkers have incremental predictive value over classical

ones,

448

but the net reclassification improvement is still only modest

(7 18%) compared, for example, with the coronary calcium score,

which has a net reclassification improvement of 66%.

449

Only subjects at high event risk should be considered for further

non-invasive or invasive testing. There are no data on how to manage

asymptomatic subjects who receive testing and have a positive test

result beyond the recommendations listed in these Guidelines.

However, the principles of risk stratification, as described above for

symptomatic patients, also apply to these individuals.

450

It is impor-

tant to remember that data demonstrating improved prognosis fol-

lowing appropriate management based on new biomarkers are still

lacking.

It is important to note that patients with cancer and undergoing

cancer treatment, or chronic inflammatory diseases such as inflam-

matory bowel diseases, rheumatoid arthritis, and systemic lupus

erythematosus, may deserve more intensive risk screening, counsel-

ling, and management.

451454

Persons whose occupations involve public safety (e.g. airline

pilots, or lorry or bus drivers), or who are professional or high-

profile athletes, commonly undergo periodic testing for the assess-

ment of exercise capacity and evaluation of possible heart disease,

including CAD. Although there are insufficient data to justify this

approach, these evaluations may be done for medicolegal reasons.

The threshold for performing an imaging test in such persons may

be lower than in the average patient. Otherwise, the same consid-

erations as discussed above for other asymptomatic persons apply

to these individuals.

Recommendations for screening for coronary artery disease in asymptomatic subjects

Recommendations Class

Level

Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults >40 years

of age without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia. IC

Assessment of family history of premature CVD (deﬁned as a fatal or non-fatal CVD event, or/and established diagnosis of

CVD in ﬁrst-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as

part of cardiovascular risk assessment.

It is recommended that all individuals aged <50 years with a family history of premature CVD in a ﬁrst-degree relative

(<55 years of age in men or <65 years of age in women) or familial hypercholesterolaemia are screened using a validated

clinical score.

455,456

Assessment of coronary artery calcium score with computed tomography may be considered as a risk modiﬁer

in the

cardiovascular risk assessment of asymptomatic subjects.

449,457

IIb B

Atherosclerotic plaque detection by carotid artery ultrasound may be considered as a risk modiﬁer

in the cardiovascular

risk assessment of asymptomatic subjects.

458

IIb B

ABI may be considered as a risk modiﬁer

in cardiovascular risk assessment.

459

IIb B

In high-risk asymptomatic adults (with diabetes, a strong family history of CAD, or when previous risk-assessment tests

suggest a high risk of CAD), functional imaging or coronary CTA may be considered for cardiovascular risk assessment. IIb C

In asymptomatic adults (including sedentary adults considering starting a vigorous exercise programme), an exercise ECG

may be considered for cardiovascular risk assessment, particularly when attention is paid to non-ECG markers such as

exercise capacity.

IIb C

Carotid ultrasound IMT for cardiovascular risk assessment is not recommended.

460

III A

In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia are not indicated for fur-

ther diagnostic assessment. III C

Routine assessment of circulating biomarkers is not recommended for cardiovascular risk stratiﬁcation.

448,449,461,462

III B

ABI = ankle-brachial index; CAD = coronary artery disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG =

electrocardiogram; IMT = intima-media thickness; SCORE = Systematic COronary Risk Evaluation.

Class of recommendation.

Level of evidence.

Reclassiﬁes patients better into low- or high-risk groups.

ESC Guidelines 43

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8 Chronic coronary syndromes in

specific circumstances

8.1 Cardiovascular comorbidities

8.1.1 Hypertension

Hypertension is the most prevalent cardiovascular risk factor and is

closely associated with CCS. Thresholds for the definition of hyperten-

sion are provided in Table 10 . BP lowering can significantly reduce major

cardiovascular risk, including CHD. Meta-analysis suggests that for every

10 mmHg reduction in systolic BP, CAD can be reduced by 17%.

463

More intensive BP targets (office BP <130 mmHg) have been associated

with favourable outcomes and are endorsed by the 2018 ESC/ESH

Guidelines for the management of arterial hypertension.

464

It is recom-

mended treat hypertensive patients with CCS are treated to office tar-

gets of 130/80 mmHg, because an increased systolic BP of > _140 mmHg

and diastolic BP of > _80 mmHg, but also a systolic BP of <120 mmHg

and diastolic BP of <70 mmHg, are associated with increased risk

465,466

(Table 10 ). Whether the J-curve phenomenon exists in patients with

revascularized CAD remains uncertain. In hypertensive patients with

CHD, beta-blockers and RAS blockers may improve post-MI out-

comes.

467

In patients with symptomatic angina, beta-blockers and cal-

cium antagonists are the preferred components of the drug-treatment

strategy. The combination of ACE inhibitors and ARBs is not recom-

mended for the treatment of hypertension because of increased renal

adverse events without beneficially influencing outcome.

468, 469

8.1.2 Valvular heart disease (including planned

transcatheter aortic valve implantation)

Coronary angiography for the assessment of CAD is recommended

before valve surgery or when percutaneous valvular intervention is

planned, to determine if revascularization is required. Coronary CTA

may be considered in patients with low risk for CAD, or in patients in

whom conventional ICA is technically not feasible or associated with

increased risk. The combination of PCI and transcatheter aortic valve

implantation appears feasible and safe, but more data are needed

before definite recommendations can be provided.

473,474

The routine

use of stress testing to detect CAD associated with severe sympto-

matic valvular disease is not recommended because of low diagnostic

value and potential risk. Symptom-limited stress testing in patients

with valvular heart disease appears safe, and may be useful to unmask

symptoms in asymptomatic patients or in patients with equivocal

symptoms.

475

8.1.3 After heart transplantation

The follow-up and assessment of long-term heart transplant survi-

vors requires specific know-how. Transplant CAD is largely an immu-

nological phenomenon, and remains a significant cause of morbidity

and mortality.

477

ICA is recommended for the assessment of trans-

plant CAD and should be performed annually for 5 years after trans-

plantation. If there are no significant abnormalities, angiograms can be

performed biannually thereafter. Intravascular ultrasound

Recommendations for valvular disease in chronic coro-

nary syndromes

476

Recommendations Class

Level

ICA is recommended before valve surgery and

for any of the following: history of CVD, sus-

pected myocardial ischaemia, LV systolic dys-

function, in men >40 years of age and post-

menopausal women, or one or more cardio-

vascular risk factors.

ICA is recommended in the evaluation of

moderate-to-severe functional mitral

regurgitation.

Coronary CTA should be considered as an

alternative to coronary angiography before

valve intervention in patients with severe valv-

ular heart disease and low probability of CAD.

IIa C

PCI should be considered in patients under-

going transcatheter aortic valve implantation

and coronary artery diameter stenosis >70%

in proximal segments.

IIa C

In severe valvular heart disease, stress testing

should not be routinely used to detect CAD

because of the low diagnostic yield and poten-

tial risks.

III C

CAD = coronary artery disease; CTA = computed tomography angiography;

CVD = cardiovascular disease; ICA = invasive coronary angiography; LV = left

ventricular; PCI = percutaneous coronary intervention.

Class of recommendation.

Level of evidence.

Recommendations for hypertension treatment in chronic

coronary syndromes

Recommendations Class

Level

It is recommended that ofﬁce BP is controlled

to target values: systolic BP 120 - 130 mmHg in

general and systolic BP 130 - 140 mmHg in

older patients (aged >65 years).

463467,470472

In hypertensive patients with a recent MI, beta-

blockers and RAS blockers are recommended.

467

In patients with symptomatic angina, beta-

blockers and/or CCBs are recommended.

467

The combination of ACE inhibitors and ARBs is

not recommended.

468,469

III A

ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; BP =

blood pressure; CCB = calcium channel blocker; RAS = renin-angiotensin system.

Class of recommendation.

Level of evidence.

Table 10 Blood pressure thresholds for the deﬁnition of

hypertension with different types of blood pressure

measurement

470472

Category Systolic BP

(mmHg)

Diastolic BP

(mmHg)

Ofﬁce BP >_140 and/or >_90

>_80 years of age >_160 and/or >_90

Ambulatory BP

Daytime (or awake) >_135 and/or >_85

Night-time (or asleep) >_120 and/or >_70

24 h >_130 and/or >_80

Home BP >_135 and/or >_85

BP = blood pressure.

44 ESC Guidelines

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examinations may be useful in assessing cardiac allograft vasculopathy

and plaque stability.

478

Treatment options for CAD in transplant

recipients include pharmacotherapy and revascularization. PCI in the

transplanted heart has become an established therapy.

479

8.2 Non-cardiovascular comorbidities

8.2.1 Cancer

Occurrence of CAD in patients with active cancer is increasing

451,452

as a side effect of cancer therapy (i.e. radiotherapy to the thorax/

mediastinum, cardiotoxic chemotherapy, or immunotherapies) or a

result of extended cancer therapies in elderly individuals. CAD in

patients with active cancer is associated with challenges for clinicians

as treatment decisions should be the subject of individualized discus-

sions based on life expectancy, additional comorbidities such as

thrombocytopenia, increased thrombosis and bleeding propensity,

and potential interactions between drugs used in CCS management

and antineoplastic drugs. In cancer patients with increased frailty, the

least invasive revascularization procedures are recommended. For

further information, see the ESC position paper on cancer treat-

ments and cardiovascular toxicity.

480

8.2.2 Diabetes mellitus

Diabetes mellitus confers about a two-fold increased risk for CAD

481

and, consequently, control of risk factors is recommended for the

prevention of CVD. Systolic BP in patients with diabetes should be

targeted to < _130 mmHg, if tolerated, but not <120 mmHg, and dia-

stolic BP to <80 mmHg, but not <70 mmHg.

482

Initial antihyperten-

sion treatment should consist of a combination of a RAS blocker with

a CCB or thiazide/thiazide-like diuretic. ACE inhibitors reduce albu-

minuria, and the appearance or progression of diabetic nephropathy,

more effectively than other drug classes.

482

Patients with diabetes

and CAD are considered to be at very high risk; consequently, LDL-

C should be lowered to <1.8 mmol/L (<70 mg/dL) or reduced by

>_50% if the baseline LCL-C is between 1.8 and 3.5 mmol/L (70 and

135 mg/dL).

For the majority of patients with diabetes and CAD, a

target glycated HbA1c level of <7% (<53 mmol/L) is recom-

mended.

483, 484

Large safety studies on new glucose-lowering drugs,

namely sodium-glucose co-transporter-2 and glucagon-like peptide-1

receptor agonists, have demonstrated significant reductions in cardi-

ovascular events. Indications for their clinical use are described in the

2019 ESC/European Association for the Study of Diabetes

Guidelines on diabetes mellitus, pre-diabetes, and cardiovascular

diseases.

A 12 lead ECG is recommended as part of the routine assessment

for screening for conduction abnormalities, LV hypertrophy, and

arrhythmias. The high prevalence of significant CAD and prohibitively

high cardiovascular mortality may suggest the usefulness of routine

screening for CAD (with functional imaging testing or coronary

CTA) in asymptomatic patients with diabetes, but no data have

shown an improvement in outcomes so far. Routine use of CTA in

asymptomatic patients with diabetes is therefore not recommended.

Recommendations for diabetes mellitus in chronic coro-

nary syndromes

Recommendations Class

Level

Risk factor (BP, LDL-C, and HbA1c) control

to targets is recommended in patients with

CAD and diabetes mellitus.

482484

In asymptomatic patients with diabetes melli-

tus, a periodic resting ECG is recommended

for cardiovascular detection of conduction

abnormalities, AF, and silent MI.

ACE inhibitor treatment is recommended in

CCS patients with diabetes for event

prevention.

482

The sodium-glucose co-transporter 2 inhibi-

tors empagliﬂozin, canagliﬂozin, or dapagliﬂo-

zin are recommended in patients with

diabetes and CVD.

c485487

A glucagon-like peptide-1 receptor agonist

(liraglutide or semaglutide) is recommended in

patients with diabetes and CVD.

c488490

In asymptomatic adults (age >40 years) with

diabetes, functional imaging or coronary CTA

may be considered for advanced cardiovascu-

lar risk assessment.

491,492

IIb B

ACE = angiotensin-converting enzyme; AF = atrial ﬁbrillation; BP = blood pres-

sure; CAD = coronary artery disease; CCS = chronic coronary syndromes; CTA

= computed tomography angiography; CVD = cardiovascular disease; ECG =

electrocardiogram; HbA1c = glycated haemoglobin; LDL-C = low-density lipo-

protein cholesterol; MI = myocardial infarction.

Class of recommendation.

Level of evidence.

Treatment algorithm is available in the 2019 European Society of Cardiology/

European Association for the Study of Diabetes Guidelines on diabetes mellitus,

pre-diabetes, and cardiovascular diseases.

Recommendations for active cancer in chronic coronary

syndromes

Recommendations Class

Level

Treatment decisions should be based on life

expectancy, additional comorbidities such as

thrombocytopenia, increased thrombosis pro-

pensity, and potential interactions between

drugs used in CCS management and antineo-

plastic agents.

If revascularization is indicated in highly symp-

tomatic patients with active cancer and

increased frailty, the least invasive procedure

is recommended.

CCS = chronic coronary syndromes.

Class of recommendation.

Level of evidence.

ESC Guidelines 45

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8.2.3 Chronic kidney disease

CAD is highly prevalent in patients with CKD and a growing number

of patients undergoing PCI have concomitant CKD.

493

There is a lin-

ear increase in the risk of cardiovascular mortality with decreasing

GFR.

494

Medical treatment for risk-factor control (lipids, BP, and glu-

cose) can improve outcomes. Special attention during the workup

for CKD patients with suspected obstructive CAD should be paid to

the fact that angina is less common and silent ischaemia more com-

mon.

495

Additionally, non-invasive stress testing shows reduced accu-

racy in patients with CKD.

496

The use of an iodinated contrast agent

should be minimized to prevent further deterioration of renal func-

tion. Decisions regarding diagnostic and treatment modalities should

be made accordingly. Interestingly, patients with CKD are less likely

to receive invasive management for treatment of CAD compared

with those without, although benefits of invasive management have

been reported.

497

Revascularization options in patients with CKD

include CABG and PCI. Meta-analyses suggest that CABG is associ-

ated with higher short-term risk of death, stroke, and repeat revascu-

larization, whereas PCI with a new-generation DES is associated with

a higher long-term risk of repeat revascularization.

498,499

Data on

patients on haemodialysis are very limited, making generalizable

treatment recommendations difficult.

8.2.4 Elderly

Ageing predisposes patients to a high incidence and prevalence of

CAD, in both men and women. Elderly patients (age >75 years) have

the greatest mortality and morbidity risk attributable to CCS, which

is enriched by the high prevalence of comorbidities (e.g. hyperten-

sion, diabetes mellitus, CKD, etc.).

505

Although the prevalence of eld-

erly patients with CAD is increasing, this population is usually

undertreated, underdiagnosed, and under-represented in clinical tri-

als. Elderly patients often present with atypical symptoms, which may

delay proper diagnosis. The treatment of CCS in the elderly is com-

plicated by a higher vulnerability to complications for both conserva-

tive and invasive strategies, such as bleeding, renal failure, and

neurological impairments, all of which require special attention. It is

recommended that radial access is used whenever possible to reduce

access-site complications, when choosing an invasive strategy for

patient management.

506,507

The use of DES, compared with bare-

metal stents, in combination with a short duration of DAPT is associ-

ated with significant safety and efficacy benefits in elderly

patients.

508, 509

8.3 Sex

Making up < _30% of study populations, women are widely under-

represented in cardiovascular studies.

510

This recruitment bias causes

an evidence gap, as sex-based randomized controlled studies are

lacking, and most data are extracted from meta-analyses and post hoc

analyses of trials in ACS patients. Differences in symptom presenta-

tion, the accuracy of diagnostic tests for CAD, and other factors that

lead to differential triage, evaluation, or early treatment of women

with myocardial ischaemia compared with men could contribute to

their worse outcomes.

511514

Whether there are true sex-related

differences in mortality after myocardial ischaemia, or whether they

owing to older age or a higher prevalence of coexisting diseases in

women, remains incompletely understood. It has become evident

that sex-related mortality differences are particularly apparent in

younger patients, typically those aged <60 years.

511,512,515

The rea-

sons for this age-dependent disparity in mortality remain unclear.

Women tend to be treated less aggressively than men.

515

However,

patient characteristics and treatments do not entirely account for sex

differences in outcomes, even after PCI.

512

It is therefore recom-

mended that women who present with signs suggestive of cardiac

ischaemia undergo careful investigation, as clinical symptoms might

be atypical. The diagnostic accuracy of the exercise ECG is even

lower in women than in men, which is in part related to functional

impairment, precluding some women from achieving an adequate

workload. Stress echocardiography with exercise or dobutamine

stress is an accurate, non-invasive technique for the detection of

obstructive CAD and risk among women with suspected CCS.

516

Both women and men have experienced improvements in mortality

Recommendations for chronic kidney disease in chronic

coronary syndromes

Recommendations Class

Level

It is recommended that risk factors are

controlled to target values.

500502

It is recommended that special attention is

paid to potential dose adjustments of renally

excreted drugs used in CCS.

It is recommended that the use of iodinated

contrast agents is minimized in patients with

severe CKD and preserved urine production

to prevent further deterioration.

503,504

CKD = chronic coronary disease; CCS = chronic coronary syndromes.

Class of recommendation.

Level of evidence.

Recommendations for elderly patients with chronic coro-

nary syndromes

Recommendations Class

Level

It is recommended that particular attention is

paid to side effects of drugs, intolerance, and

overdosing in elderly patients.

The use of DES is recommended in elderly

patients.

508,509

Radial access is recommended in elderly

patients to reduce access-site bleeding

complications.

506,507

It is recommended that diagnostic and revas-

cularization decisions are based on symptoms,

the extent of ischaemia, frailty, life expectancy,

and comorbidities.

DES = drug-eluting stents.

Class of recommendation.

Level of evidence.

46 ESC Guidelines

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when new-generation DES were used.

517519

The mortality reduc-

tions were similar among women and men leaving sex disparities in

outcomes unchanged.

512

Women have higher complication rates fol-

lowing CABG and may also have higher mortality risk,

520,521

espe-

cially in elderly patients. Hormone replacement therapy in post-

menopausal women does not reduce the risk of ischaemic myocar-

dial disease (see section 3.3.5), and is therefore not recommended for

primary and secondary prevention.

344,522,523

8.4 Patients with refractory angina

Refractory angina refers to long-lasting symptoms (for >_3 months)

due to established reversible ischaemia in the presence of obstructive

CAD, which cannot be controlled by escalating medical therapy with

the use of second- and third-line pharmacological agents, bypass

grafting, or stenting including PCI of chronic total coronary occlusion.

Incidence is growing with more advanced CAD, multiple comorbid-

ities, and ageing of the population. The quality of life of patients with

refractory angina is poor, with frequent hospitalization and a high

level of resource utilization. The number of potential treatment

options is increasing, but the level of evidence in support of their

safety and efficacy varies from non-existent (in the case of transmyo-

cardial laser application) to promising. RCTs with endpoints such as

the severity and frequency of angina, as well as quality of life, are

obviously needed, along with safety metrics. To confirm treatment

efficacy, trials with a sham-controlled design are desirable, a significant

placebo effect being part of the therapeutic effect. Patients with

refractory angina are best treated in dedicated 'angina clinics' by mul-

tidisciplinary teams experienced in selecting the most suitable thera-

peutic approach in the individual patient based on an accurate

diagnosis of the mechanisms of the pain syndrome. Once conven-

tional anti-ischaemic targets have been exhausted (through an

increase in nutrient blood flow delivery and/or reduction in oxygen

consumption), novel therapies can be ranked by mechanism of

action: promotion of collateral growth, transmural redistribution of

blood flow, and neuromodulation of the cardiac pain syndrome

(Table 11 ).

Both the STARTSTIM and RENEW (Efficacy and Safety of

Targeted Intramyocardial Delivery of Auto CD34 þStem Cells for

Improving Exercise Capacity in Subjects With Refractory Angina) tri-

als were underpowered due to premature study termination. Of

note, a patient-level pooled analysis of 304 patients included in three

double-blind, cell therapy, placebo-controlled trials, among which

was the RENEW trial, showed that active treatment with autologous

haematopoietic cells had significant effects on exercise time and

angina frequency.

528

Based on positive results from two RCTs in small groups of

patients, both enhanced external counterpulsation and the coronary

sinus reducer device represent alternative options in patients with

refractory angina, which is resistant after having exhausted all options

for medical therapy and mechanical revascularization. Controlled

coronary sinus narrowing with the implantation of a large stainless-

steel device increases coronary sinus pressure, leading to improved

perfusion in the LAD territory.

Total reported experience with all novel therapeutic options

remains limited, both regarding the number of treated patients and

the duration of follow-up. Larger RCTs are required to define the

role of each treatment modality for specific subgroups, to decrease

non-responder rates and ascertain benefit beyond potential placebo

effects.

Recommendation for sex issues and chronic coronary

syndromes

Recommendation Class

Level

Hormone replacement therapy is not recom-

mended for risk reduction in post-menopausal

women.

III C

Class of recommendation.

Level of evidence.

Table 11 Potential treatment options for refractory angina and summary of trial data

Therapy Type of therapy RCT Type of control group Number of

patients enrolled

External counterpulsation Enhanced external counterpulsation MUST

524

Sham 139

Extracorporeal shockwave Low-energy extracorporeal shockwave therapy Not available Not available —

Coronary sinus constriction Reducer device COSIRA

525

Sham 104

Neuromodulation Spinal cord stimulation STARTSTIM

526

Not available 68

Transcutaneous electrical neural stimulation Not available Not available —

Subcutaneous electrical neural stimulation Not available Not available —

Sympathectomy Denby et al.

527

Placebo 65

Gene therapy Adenovirus ﬁbroblast growth factor 5 Not available Not available —

Autologous cell therapy Mononuclear bone marrow-derived

haematopoietic progenitor cells

RENEW

528

Placebo 112

RCT = randomized clinical trial.

ESC Guidelines 47

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9 Key messages

(1) Careful evaluation of patient history, including the characterization

of anginal symptoms, and evaluation of risk factors and manifesta-

tions of CVD, as well as proper physical examination and basic

testing, are crucial for the diagnosis and management of CCS.

(2) Unless obstructive CAD can be excluded based on clinical evalua-

tion alone, either non-invasive functional imaging or anatomical

imaging using coronary CTA may be used as the initial test to rule-

out or establish the diagnosis of CCS.

(3) Selection of the initial non-invasive diagnostic test is based on the

PTP, the test's performance in ruling-in or ruling-out obstructive

CAD, patient characteristics, local expertise, and the availability of

the test.

(4) For revascularization decisions, both anatomy and functional eval-

uation are to be considered. Either non-invasive or invasive func-

tional evaluation is required for the assessment of myocardial

ischaemia associated with angiographic stenosis, unless very high

grade (>90% diameter stenosis).

(5) Assessment of risk serves to identify CCS patients at high event risk

who are projected to derive prognostic benefit from revasculariza-

tion. Risk stratification includes the assessment of LV function.

(6) Patients at high event riskshouldundergo invasiveinvestigation for

consideration of revascularization, even if they have mild or no

symptoms.

(7) Implementation of healthy lifestyle behaviours decreases the risk

of subsequent cardiovascular events and mortality, and is addi-

tional to appropriate secondary prevention therapy. Clinicians

should advise on and encourage necessary lifestyle changes in

every clinical encounter.

(8) Cognitive behavioural interventions such as supporting patients to

set realistic goals, self-monitor, plan how to implement changes

and deal with difficult situations, set environmental cues, and

engage social support are effective interventions for behaviour

change.

(9) Multidisciplinary teams can provide patients with support to make

healthy lifestyle changes, and address challenging aspects of behav-

iour and risk.

(10) Anti-ischaemic treatment must be adapted to the individual patient

based on comorbidities, co-administered therapies, expected tol-

erance and adherence, and patient preferences. The choice of

anti-ischaemic drugs to treat CCS should be adapted to the

patient's heart rate, BP, and LV function.

(11) Beta-blockers and/or CCBs remain the first-line drugs in patients

with CCS. Beta-blockers are recommended in patients with LV

dysfunction or HF with reduced ejection fraction.

(12) Long-acting nitrates provoke tolerance with loss of efficacy. This

requires prescription of a daily nitrate-free or nitrate-low interval

of  10 14 h.

(13) Antithrombotic therapy is a key part of secondary prevention in

patients with CCS and warrants careful consideration. Patients

with a previous MI, who are at high risk of ischaemic events and

low risk of fatal bleeding, should be considered for long-term

DAPT with aspirin and either a P2Y

inhibitor or very low-dose

rivaroxaban, unless they have an indication for an OAC such as

AF.

(14) Statins are recommended in all patients with CCS. ACE inhibitors

(or ARBs) are recommended in the presence of HF, diabetes, or

hypertension and should be considered in high-risk patients.

(15) Proton pump inhibitors are recommended in patients receiving

aspirin or combination antithrombotic therapy who are at high

risk of gastrointestinal bleeding.

(16) Efforts should be made to explain to patients the importance of

evidence-based prescriptions to increase adherence to treatment,

and repeated therapeutic education is essential in every clinical

encounter.

(17) Patients with a long-standing diagnosis of CCS should undergo

periodic visits to assess potential changes in risk status, adherence

to treatment targets, and the development of comorbidities.

Repeat stress imaging or ICA with functional testing is recom-

mended in the presence of worsening symptoms and/or increased

risk status.

(18) Assessment of myocardial and valvular function and dimensions, as

well as a functional test to rule-out significant myocardial silent

ischaemia, may be contemplated every 3 5 years in asymptomatic

patients with a long-standing diagnosis of CCS.

Recommendations for treatment options for refractory angina

Recommendations Class

Level

Enhanced external counterpulsation may be considered for symptom relief in patients with debilitating angina refractory

to optimal medical and revascularization strategies.

524

IIb B

A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refrac-

tory to optimal medical and revascularization strategies.

525

IIb B

Spinal cord stimulation may be considered to ameliorate symptoms and quality of life in patients with debilitating angina

refractory to optimal medical and revascularization strategies.

526

IIb B

Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical

and revascularization strategies.

529

III A

Class of recommendation.

Level of evidence.

48 ESC Guidelines

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(19) An assessment of coronary vasomotor function should be consid-

ered in patients with non-significant epicardial CAD and objective

evidence of ischaemia.

10 Gaps in the evidence

10.1 Diagnosis and assessment

More information on the effects of various risk factors, biomarkers,

and comorbidities on the PTP of obstructive CAD is needed.

Adequately powered RCTs are needed to compare the effectiveness

of different diagnostic strategies, and to evaluate how to best inte-

grate diagnostic tests in patient carein terms of clinical outcomes and

the use of healthcare resources.

10.2 Assessment of risk

Studies should address whether an initial invasive strategy, in addition

to optimal medical therapy in patientswith CCSand inducible ischae-

mia by non-invasive testing, improves outcomes. Larger trials are

needed to verify the utility of systematic assessment of biomarkers in

patients with suspected obstructive CAD.

10.3 Lifestyle management

Research regarding the most effective methods to support healthy

lifestyle behaviours in brief or very brief clinical encounters, and sus-

tain medication and lifestyle behaviour adherence over time, is

needed. The cardiovascular effects of newer e-cigarettes over the

long-term remain unknown, as does their effectiveness in smoking

cessation.

The relative benefits of high-intensity interval training vs.

moderate-intensity exercise in patients with CCS should be further

evaluated. The benefits of decreasing sedentary behaviour, and the

most appropriate 'dose' and type of physical activity in patients with

CCS, are unknown, as are the effectiveness and cost-effectiveness of

increasing cardiac rehabilitation participation among patients with

CCS.

10.4 Pharmacological management

The need for and duration of beta-blocker therapy following MI to

maintain a protective effect on cardiac events in the absence of LV

systolic dysfunction are unknown.

In patients with CCS and without a previous MI, it remains to be

determined whether current anti-ischaemic drugs improve

prognosis.

Whether the initial use of second-line anti-ischaemic therapy (i.e.

long-acting nitrates, ranolazine, nicorandil, ivabradine, or trimetazi-

dine) alone or in combination with a first-line drug (i.e. beta-blocker

or CCB) is superior to the combination of a beta-blocker with a CCB

to control anginal symptoms and myocardial ischaemia in patients

with CCS remains to be proven.

The efficacy and safety of aspirin or an alternative antithrombotic

therapy in patients with a mild extent of atherosclerotic disease, such

as that discovered by coronary CTA, requires further assessment,

including the effect on cancer rates as well as cardiovascular events.

The optimal long-term antithrombotic therapy, and strategies for

individualizing this, in patients at high risk of ischaemic events is uncer-

tain. Consequently, clinical studies comparing the efficacy and safety

of aspirin þ P2Y

inhibitor with aspirin þ factor Xa inhibitor are

warranted to determine which subgroups may be preferentially

treated with one or other strategy. The potential clinical benefit of

ticagrelor monotherapy, while stopping aspirin, remains unproved at

present.

The role of biomarkers in stratifying patients' risk of ischaemic

events and bleeding requires clarification, including the role of growth

differentiation factor-15 in guiding the risk of bleeding with DAPT. It

is uncertain what effect novel lipid-lowering strategies will have on

the net clinical benefit of DAPT, with similar implications of other

strategies such as intensive BP lowering and, potentially in the future,

selective anti-inflammatory therapies.

10.5 Revascularization

Further studies, including RCTs, are needed to assess the value of

functional vs. anatomical guidance for CABG. The concept of com-

plete revascularization and its effect on prognosis needs to be re-

evaluated by prospective comparisons of functional vs. anatomical

guidance for stenting on the one hand, and bypass on the other. Of

note, none of the RCTs comparing PCI with CABG to date have

used combined anatomical and functional guidance for PCI, a strategy

that is suggested to significantly improve outcomes of PCI (Syntax II

registry).

10.6 Heart failure and left ventricular

dysfunction

Most of the evidence from RCTs supporting the recommendations

for the use of drugs and devices in patients with chronic heart failure

is based on cohorts with stable ischaemic heart disease and reduced

LV function. However, patients with CCS requiring acute or chronic

mechanical support are largely excluded from clinical trials, and the

optimal management of such patients with drugs and devices during

episodes of acute decompensation has not been adequately

addressed.

10.7 Patients with long-standing diagno-

sis of chronic coronary syndromes

The incremental value of using risk scores to serially evaluate

patients' risks, and more importantly to adjust the intensity of treat-

ment, remains to be determined.

The optimal time intervals for serial visits remain to be

determined.

10.8 Angina without obstructive

coronary artery disease

Development of safe and efficacious novel pharmacological agents

for this indication remains an unmet need.

10.9 Screening in asymptomatic subjects

Further studies on biomarkers and imaging tests for screening of

CAD in asymptomatic subjects are needed. Furthermore, there are

limited data on how to manage asymptomatic subjects who receive

testing and have a positive test result, as evidence demonstrating

improved prognosis following appropriate management is still

lacking.

ESC Guidelines 49

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10.10 Comorbidities

The role of PCIin patients with aortic stenosis remains undetermined

with respect to the indication for coronary revascularization and tim-

ing vs. valve intervention. Further information is needed on how to

adapt cardiovascular therapies in patients with chronic inflammatory

diseases.

10.11 Patients with refractory angina

Larger RCTs and registries are required to define the role of additional

treatment modalities for specific subgroups, to decrease non-

responder rates and ascertain benefit beyond potential placebo effects.

Recommendations: 'what to do' and 'what not to do' Class

Level

Basic biochemistry testing in the initial diagnostic management of patients with suspected CAD

If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or

ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS. IA

The following blood tests are recommended in all patients:

•Full blood count (including haemoglobin); IB

•Creatinine measurement and estimation of renal function; IA

•A lipid proﬁle (including LDL-C). IA

It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-

mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c

and fasting plasma glucose results are inconclusive.

Assessment of thyroid function is recommended in cases where there is clinical suspicion of thyroid disorders. IC

Resting ECG in the initial diagnostic management of patients with suspected CAD

A resting 12 lead ECG is recommended in all patients with chest pain without obvious non-cardiac cause. IC

A resting 12 lead ECG is recommended in all patients during or immediately after an episode of angina suspected to indi-

cate clinical instability of CAD. IC

ST-segment alterations recorded during supraventricular tachyarrhythmias should not be used as evidence of CAD. III C

Ambulatory ECG monitoring in the initial diagnostic management of patients with suspected CAD

Ambulatory ECG monitoring is recommended in patients with chest pain and suspected arrhythmias. IC

Ambulatory ECG monitoring should not be used as routine examination in patients with suspected CCS. III C

Resting echocardiography and CMR in the initial diagnostic management of patients with suspected CAD

A resting transthoracic echocardiogram is recommended in all patients for:

•Exclusion of alternative causes of angina;

•Identiﬁcation of regional wall motion abnormalities suggestive of CAD;

•Measurement of LVEF for risk-stratiﬁcation purposes;

•Evaluation of diastolic function.

Chest X-ray in the initial diagnostic management of patients with suspected CAD

Chest X-ray is recommended for patients with an atypical presentation, signs and symptoms of heart failure, or suspicion

of pulmonary disease. IC

Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected CAD

Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnos-

ing CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone. IB

It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD

and other patient characteristics that inﬂuence test performance, local expertise, and the availability of tests. IC

Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-

niﬁcance or is not diagnostic. IB

Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and

severe symptoms refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indi-

cates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revasculariza-

tion, unless very high grade (>90% diameter stenosis).

Continued

11 'What to do' and 'what not to do' messages from the Guidelines

50 ESC Guidelines

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Coronary CTA is not recommended when extensive coronary calciﬁcation, irregular heart rate, signiﬁcant obesity, inabil-

ity to cooperate with breath-hold commands, or any other conditions makes good image quality unlikely. III C

Coronary calcium detection by computed tomography is not recommended to identify individuals with obstructive CAD. III C

Performing exercise ECG in the initial diagnostic management of patients with suspected CAD

Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event

risk in selected patients. IC

Recommendations for risk assessment

Risk stratiﬁcation is recommended based on clinical assessment and the result of the diagnostic test initially employed to

make a diagnosis of CAD. IB

Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. IC

Risk stratiﬁcation, preferably using stress imaging or coronary CTA (if local expertise and availability permit), or alterna-

tively exercise stress ECG (if signiﬁcant exercise can be performed and the ECG is amenable to the identiﬁcation of

ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.

In symptomatic patients with a high-risk clinical proﬁle, ICA complemented by invasive physiological guidance (FFR) is rec-

ommended for cardiovascular risk stratiﬁcation, particularly if the symptoms are inadequately responding to medical treat-

ment and revascularization is considered for improvement of prognosis.

In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended

for patients undergoing medical treatment in whom non-invasive risk stratiﬁcation indicates a high event risk and revascu-

larization is considered for the improvement of prognosis.

ICA is not recommended solely for risk stratiﬁcation. III C

Recommendations on lifestyle management

Improvement of lifestyle factors in addition to appropriate pharmacological management is recommended. IA

Cognitive behavioural interventions are recommended to help individuals achieve a healthy lifestyle. IA

Exercise-based cardiac rehabilitation is recommended as an effective means for patients with CCS to achieve a healthy

lifestyle and manage risk factors. IA

Involvement of multidisciplinary healthcare professionals (cardiologists, GPs, nurses, dieticians, physiotherapists, psycholo-

gists, and pharmacists) is recommended. IA

Psychological interventions are recommended to improve symptoms of depression in patients with CCS. IB

Annual inﬂuenza vaccination is recommended for patients with CCS, especially in the elderly. IB

Recommendations on anti-ischaemic drugs in patients with CCS

General considerations

Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with

drug(s) for event prevention. IC

It is recommended that patients are educated about the disease, risk factors, and treatment strategy. IC

Timely review of the patient's response to medical therapies (e.g. 2 4 weeks after drug initiation) is recommended. IC

Angina/ischaemia relief

Short-acting nitrates are recommended for immediate relief of effort angina. IB

First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms. IA

Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy or co-administration of phos-

phodiesterase inhibitors. III B

Recommendations for event prevention

Antithrombotic therapy in patients with CCS and in sinus rhythm

Aspirin 75 100 mg daily is recommended in patients with a previous MI or revascularization. IA

Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance. IB

Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm

Aspirin 75 100 mg daily is recommended following stenting. IA

Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg, >5 days, or maintenance therapy) is recommended, in

addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (13

months) is indicated due to the risk or occurrence of life-threatening bleeding.

Antithrombotic therapy in patients with CCS and AF

When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in pref-

erence to a VKA. IA

Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF

and a CHA

-VASc score >_2 in males and >_3 in females. IA

Continued

ESC Guidelines 51

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Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC

It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent

implantation. IC

In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d.,

edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy. IA

The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C

Use of proton pump inhibitors

Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC

monotherapy who are at high risk of gastrointestinal bleeding. IA

Lipid-lowering drugs

Statins are recommended in all patients with CCS. IA

If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended. IB

For patients at very high risk who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combi-

nation with a PCSK9 inhibitor is recommended. IA

ACE inhibitors

ACE inhibitors (or ARBs) are recommended in the presence of other conditions (e.g. HF, hypertension, or diabetes). IA

Other drugs

Beta-blockers are recommended in patients with LV dysfunction or systolic HF. IA

General recommendations for the management of patients with CCS and symptomatic HF due to ischaemic cardiomyopathy and LV

systolic dysfunction

Recommendations for drug therapy

Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF

symptoms. IB

Beta-blockers are recommended as an essential component of treatment due to their efﬁcacy in both relieving angina, and

reducing morbidity and mortality in HF. IA

ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to

improve symptoms and reduce morbidity and mortality. IA

An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition or an angiotensin recep-

tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy. IB

An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and

beta-blocker to reduce morbidity and mortality. IA

For devices, comorbidities, and revascularization

In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker

rather than right ventricular pacing is recommended. IA

An implantable cardioverter-deﬁbrillator is recommended in patients with documented ventricular dysrhythmia causing

haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF <_35%, to

reduce the risk of sudden death and all-cause mortality.

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration >_150 ms and LBBB QRS

morphology, and with LVEF <_35% despite optimal medical therapy to improve symptoms and reduce morbidity and mor-

tality.

355,356,383392,353,354,381390

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration 130 149 ms and LBBB

QRS morphology, and with LVEF <_35% despite optimal medical therapy to improve symptoms and reduce morbidity and

mortality.

355,356,383392,353,354,381390

Comprehensive risk proﬁling and multidisciplinary management, including treatment of major comorbidities such as

hypertension, hyperlipidaemia, diabetes, anaemia, and obesity, as well as smoking cessation and lifestyle modiﬁcation, are

recommended.

Myocardial revascularization is recommended when angina persists despite treatment with antianginal drugs. IA

Recommendations for patients with a long-standing diagnosis of CCS

Asymptomatic patients

A periodic visit to a cardiovascular healthcare professional is recommended to reassess potential changes in the risk status

of patients, entailing clinical evaluation of lifestyle-modiﬁcation measures, adherence to targets of cardiovascular risk fac-

tors, and the development of comorbidities that may affect treatments and outcomes.

Continued

52 ESC Guidelines

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In patients with mild or no symptoms receiving medical treatment, in whom non-invasive risk stratiﬁcation indicates a high

risk, and for whom revascularization is considered for improvement of prognosis, ICA (with FFR when necessary) is

recommended.

Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C

ICA is not recommended solely for risk stratiﬁcation. III C

Symptomatic patients

Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed

to a reversible cause (e.g. long-standing tachycardia or myocarditis). IC

Risk stratiﬁcation is recommended for patients with new or worsening symptom levels, preferably using stress imaging or,

alternatively, exercise stress ECG. IB

It is recommended that patients with signiﬁcant worsening of symptoms be expeditiously referred for evaluation. IC

ICA (with FFR/iwFR when necessary) is recommended for risk stratiﬁcation in patients with severe CAD, particularly if

the symptoms are refractory to medical treatment or if they have a high-risk clinical proﬁle. IC

Investigations in patients with suspected vasospastic angina

An ECG is recommended during angina if possible. IC

Invasive angiography or coronary CTA is recommended in patients with characteristic episodic resting angina and ST-seg-

ment changes, which resolve with nitrates and/or calcium antagonists, to determine the extent of underlying coronary

disease.

Screening for CAD in asymptomatic subjects

Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults aged >40

years without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia. IC

Assessment of family history of premature CVD (deﬁned as a fatal or non-fatal CVD event, and/or established diagnosis of

CVD in ﬁrst-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as

part of cardiovascular risk assessment.

It is recommended that all individuals aged <50 years with a family history of premature CVD in a ﬁrst-degree relative

(<55 years of age in men, <65 years of age in women) are screened for familial hypercholesterolaemia using a validated

clinical score.

Carotid ultrasound IMT for cardiovascular risk assessment is not recommended. III A

In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia is not indicated for fur-

ther diagnostic assessment. III C

Routine assessment of circulating biomarkers is not recommendedfor cardiovascular risk stratiﬁcation. III B

Recommendations for hypertension treatment in CCS

It is recommended that ofﬁce BP be controlled to target values: systolic BP 120 130 mmHg in general and systolic BP

130 140 mmHg in older patients (aged >65 years). IA

In hypertensive patients with a recent MI, beta-blockers and RAS blockers are recommended. IA

In patients with symptomatic angina, beta-blockers and/or CCBs are recommended. IA

The combination of ACE inhibitors and an ARB is not recommended. III A

Recommendations for valvular disease in CCS

ICA is recommended before valve surgery and any of the following: history of CVD, suspected myocardial ischaemia, LV

systolic dysfunction, in men aged >40 years and post-menopausal women, or one or more cardiovascular risk factors. IC

ICA is recommended in the evaluation of moderate-to-severe functional mitral regurgitation. IC

In severe valvular heart disease, stress testing should not be routinely used to detect CAD because of the low diagnostic

yield and potential risks. III C

Recommendations for active cancer in CCS

Treatment decisions should be based on life expectancy, additional comorbidities such as thrombocytopenia, increased

thrombosis propensity, and potential interactions between drugs used in CCS management and antineoplastic agents. IC

If revascularization is indicated in highly symptomatic patients with active cancer and increased frailty, the least invasive

procedure is recommended. IC

Recommendations for diabetes mellitus in CCS

Risk factor (BP, LDL-C, and HbA1c) control to targets is recommended in patients with CAD and diabetes mellitus. IA

In asymptomatic patients with diabetes mellitus, a periodic resting ECG is recommended for cardiovascular detection of

conduction abnormalities, AF, and silent MI. IC

Continued

ESC Guidelines 53

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12 Supplementary data

Supplementary Data with additional Supplementary Tables and Figures

complementing the full text—as well as section 3 on patients with angina

and/or dyspnoea, and suspected coronary artery disease—are available

on the European Heart Journal website and via the ESC website at www.

escardio.org/guidelines.

13 Appendix

Author/Task Force Member affiliations:

Stephan Achenbach, Department of Cardiology, Friedrich-

Alexander-Universit€

at Erlangen-Nu¨rnberg, Erlangen, Germany; Stefan

Agewall, Department of Medicine, Clinical Science, Oslo, Norway;

Emanuele Barbato, Advanced Biomedical Sciences, University

Federico II, Naples, Italy; Jeroen J. Bax , Cardiology, Leiden University

Medical Center, Leiden, Netherlands; Davide Capodanno ,

CardioThoracic-Vascular and Transplant Department, A.O.U.

'Policlinico-Vittorio Emanuele', University of Catania, Catania, Italy;

Thomas Cuisset, Cardiology, CHU Timone, Marseille, France;

Christi Deaton,PublicHealthandPrimaryCare,Universityof

Cambridge School of Clinical Medicine, Cambridge, United Kingdom;

Kenneth Dickstein, Cardiology, Stavanger University Hospital,

University of Bergen, Stavanger, Norway; Thor Edvardsen ,

Cardiology, Oslo University Hospital, Oslo, Norway; Javier Escaned ,

Interventional Cardiology Unit, Hospital Clinico San Carlos, Madrid,

Spain; Christian Funck-Brentano , Department of Clinical

Pharmacology, Sorbonne Universite ´ , AP-HP, ICAN and INSERM CIC

Paris-Est, Paris, France; Bernard J. Gersh ,Departmentof

Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of

America; Martine Gilard , Cardiology, Brest University, Brest, France;

David Hasdai, Cardiology, Rabin Medical Center Petah Tikva, Israel;

Robert Hatala , Department of Cardiology and Angiology, Slovak

Cardiovascular Institute, Slovak Medical University, Bratislava, Slovakia;

Felix Mahfoud, Internal Medicine III, Saarland University, Homburg,

Germany; Josep Masip , Cardiology Department /Intensive Care

Department, Hospital CIMA-Sanitas/Consorci Sanitari Integral/

University of Barcelona, Barcelona, Spain; Claudio Muneretto ,

Cardiovascular Surgery, University of Brescia Medical School, Brescia,

Italy; Eva Prescott , Department of Cardiology, Bispebjerg University

Hospital, Copenhagen, Denmark; Antti Saraste, Heart Center, Turku

University Hospital, Turku, Finland; Robert F. Storey,Departmentof

Infection, Immunity and Cardiovascular Disease, University of Sheffield,

Sheffield, United Kingdom; Pavel Svitil , Cardiologic Practice, Practice

of General Cardiology, Jihlava, Czech Republic; Marco Valgimigli ,

Inselspital, University of Bern, Bern, Switzerland.

Treatment with ACE inhibitors is recommended in CCS patients with diabetes for event prevention. IB

The sodium-glucose co-transporter 2 inhibitors empagliﬂozin, canagliﬂozin, or dapagliﬂozin are recommended in patients

with diabetes and CVD. IA

A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes and

CVD. IA

Recommendations for CKD in CCS

It is recommended that risk factors are controlled to target values. IA

It is recommended that special attention be paid to potential dose adjustments of renally excreted drugs used in CCS. IC

It is recommended that the use of iodinated contrast agents is minimized in patients with severe CKD and preserved urine

production to prevent further deterioration. IB

Recommendations for elderly patients with CCS

It is recommended that particular attention is paid to side effects of drugs, intolerance, and overdosing in elderly patients. IC

The use of DES is recommended in elderly patients. IA

Radial access is recommended in elderly patients to reduce access-site bleeding complications. IB

It is recommended that diagnostic and revascularization decisions are based on symptoms, the extent of ischaemia, frailty,

life expectancy, and comorbidities. IC

Recommendation for sex issues and CCS

Hormone replacement therapy is not recommended for risk reduction in post-menopausal women. III C

Treatment options in refractory angina

Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical

and revascularization strategies. III A

ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial ﬁbrillation; ARB = angiotensin receptor blocker; b.i.d. = bis in die (twice a day); BP =

blood pressure; CHA

-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 65 74 and Sex category [Female];

CAD = coronary artery disease; CCB = calcium channel blocker; CCS = chronic coronary syndromes; CKD = chronic kidney disease; CMR = cardiac magnetic resonance;

CRT = cardiac resynchronization therapy; CTA = computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DES = drug-eluting

stent; ECG = electrocardiogram; FFR = fractional ﬂow reserve; GPs = general practitioners; HbA1C = glycated haemoglobin; HF = heart failure; ICA = invasive coronary

angiography; IMT = intima-media thickness; iwFR = instantaneous wave-free ratio (instant ﬂow reserve); LBBB = left bundle branch block; LDL-C = low-density lipoprotein cho-

lesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antag-

onist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin

type 9; RAS = renin-angiotensin system; VKA = vitamin K antagonist.

Class of recommendation.

Level of evidence.

54 ESC Guidelines

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ESC Committee for Practice Guidelines (CPG): Stephan

Windecker (Chairperson) (Switzerland), Victor Aboyans (France),

Colin Baigent (United Kingdom), Jean-Philippe Collet (France),

Veronica Dean (France), Victoria Delgado (Netherlands), Donna

Fitzsimons (United Kingdom), Christopher P. Gale (United

Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen

(Norway), Gerhard Hindricks (Germany), Bernard Iung (France),

Peter Ju¨ni (Canada), Hugo A. Katus (Germany), Ulf Landmesser

(Germany), Christophe Leclercq (France), Maddalena Lettino (Italy),

Basil S. Lewis (Israel), Bela Merkely (Hungary), Christian Mueller

(Switzerland), Steffen Petersen (United Kingdom), Anna Sonia

Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi

(Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A.

Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M.

Touyz (United Kingdom).

ESC National Cardiac Societies actively involved in the review

process of the 2019 ESC Guidelines for the diagnosis and manage-

ment of chronic coronary syndromes.

Algeria: Algerian Society of Cardiology, Salim Benkhedda;

Austria: Austrian Society of Cardiology, Bernhard Metzler;

Belarus: Belorussian Scientific Society of Cardiologists, Volha

Sujayeva; Belgium: Belgian Society of Cardiology, Bernard

Cosyns; Bosnia and Herzegovina: Association of Cardiologists

of Bosnia and Herzegovina, Zumreta Kusljugic; Bulgaria: Bulgarian

Society of Cardiology, Vasil Velchev; Cyprus: Cyprus Society of

Cardiology, Georgios Panayi; Czech Republic: Czech Society of

Cardiology, Petr Kala; Denmark: Danish Society of Cardiology,

Sune Ammentorp Haahr-Pedersen; Egypt: Egyptian Society of

Cardiology, Hamza Kabil; Estonia: Estonian Society of Cardiology,

Tiia Ainla; Finland: Finnish Cardiac Society, Tomi Kaukonen;

France: French Society of Cardiology, Guillaume Cayla; Georgia:

Georgian Society of Cardiology, Zurab Pagava; Germany:

German Cardiac Society, Jochen Woehrle; Greece: Hellenic

Society of Cardiology, John Kanakakis; Hungary: Hungarian

Society of Cardiology, K

alm

an T

oth; Iceland: Icelandic Society of

Cardiology, Thorarinn Gudnason; Ireland: Irish Cardiac Society,

Aaron Peace; Israel: Israel Heart Society, Doron Aronson; Italy:

Italian Federation of Cardiology, Carmine Riccio; Kosovo

(Republic of): Kosovo Society of Cardiology, Shpend Elezi;

Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov;

Latvia: Latvian Society of Cardiology, Silvija Hansone; Lebanon:

Lebanese Society of Cardiology, Antoine Sarkis; Lithuania:

Lithuanian Society of Cardiology, Ruta Babarskiene;

Luxembourg: Luxembourg Society of Cardiology, Jean Beissel;

Malta: Maltese Cardiac Society, Andrew J. Cassar Maempel;

Moldova (Republic of): Moldavian Society of Cardiology, Valeriu

Revenco; Netherlands : Netherlands Society of Cardiology, G.J.

de Grooth; North Macedonia : Macedonian FYR Society of

Cardiology, Hristo Pejkov; Norway: Norwegian Society of

Cardiology, Vibeke Juliebø; Poland: Polish Cardiac Society, Piotr

Lipiec; Portugal: Portuguese Society of Cardiology, Jose´ Santos;

Romania: Romanian Society of Cardiology, Ovidiu Chioncel;

Russian Federation: Russian Society of Cardiology, Dmitry

Duplyakov; San Marino: San Marino Society of Cardiology, Luca

Bertelli; Serbia: Cardiology Society of Serbia, Ana Djordjevic

Dikic; Slovakia: Slovak Society of Cardiology, Martin Studen

can;

Slovenia: Slovenian Society of Cardiology, Matjaz Bunc; Spain:

Spanish Society of Cardiology, Fernando Alfonso; Sweden:

Swedish Society of Cardiology, Magnus B€

ack; Switzerland: Swiss

Society of Cardiology, Michael Zellweger; Tunisia: Tunisian

Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad;

Turkey: Turkish Society of Cardiology, Aylin Yildirir; Ukraine:

Ukrainian Association of Cardiology, Yuriy Sirenko; United

Kingdom of Great Britain and Northern Ireland: British

Cardiovascular Society, Brian Clapp.

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Importance Cardiac telerehabilitation (CTR) has been found to be a safe and beneficial alternative to traditional center-based cardiac rehabilitation (CR) and might be associated with higher participation rates by reducing barriers to CR use. However, implementation of CTR interventions remains low, which may be owing to a lack of cost-effectiveness analyses of data from large-scale randomized clinical trials. Objective To assess the cost-effectiveness of CTR with relapse prevention compared with center-based CR among patients with coronary artery disease. Design, Setting, and Participants This economic evaluation performed a cost-utility analysis of data from the SmartCare-CAD (Effects of Cardiac Telerehabilitation in Patients With Coronary Artery Disease Using a Personalized Patient-Centred ICT Platform) randomized clinical trial. The cost-effectiveness and utility of 3 months of cardiac telerehabilitation followed by 9 months of relapse prevention were compared with the cost-effectiveness of traditional center-based cardiac rehabilitation. The analysis included 300 patients with stable coronary artery disease who received care at a CR center serving 2 general hospitals in the Netherlands between May 23, 2016, and July 26, 2018. All patients were entering phase 2 of outpatient CR and were followed up for 1 year (until August 14, 2019). Data were analyzed from September 21, 2020, to September 24, 2021. Intervention After baseline measurements were obtained, participants were randomly assigned on a 1:1 ratio to receive CTR (intervention group) or center-based CR (control group) using computerized block randomization. After 6 supervised center-based training sessions, patients in the intervention group continued training at home using a heart rate monitor and accelerometer. Patients uploaded heart rate and physical activity data and discussed their progress during a weekly video consultation with their physical therapist. After 3 months, weekly coaching was concluded, and on-demand coaching was initiated for relapse prevention; patients were instructed to continue using their wearable sensors and were contacted in cases of nonadherence to the intervention or reduced exercise or physical activity volumes. Main Outcomes and Measures Quality-adjusted life-years were assessed using the EuroQol 5-Dimension 5-Level survey (EQ-5D-5L) and the EuroQol Visual Analogue Scale (EQ-VAS), and cardiac-associated health care costs and non–health care costs were measured by health care consumption, productivity, and informal care questionnaires (the Medical Consumption Questionnaire, the Productivity Cost Questionnaire, and the Valuation of Informal Care Questionnaire) designed by the Institute for Medical Technology Assessment. Costs were converted to 2020 price levels (in euros) using the Dutch consumer price index (to convert to US dollars, euro values were multiplied by 1.142, which was the mean exchange rate in 2020). Results Among 300 patients (266 men [88.7%]), the mean (SD) age was 60.7 (9.5) years. The quality of life among patients receiving CTR vs center-based CR was comparable during the study according to the results of both utility measures (mean difference on EQ-5D-5L: −0.004; P = .82; mean difference on EQ-VAS: −0.001; P = .92). Intervention costs were significantly higher for CTR (mean [SE], €224 [€4] [$256 ($4)]) compared with center-based CR (mean [SE], €156 [€5] [$178 ($6)]; P < .001); however, no difference in overall cardiac health care costs was observed between CTR (mean [SE], €4787 [€503] [$5467 ($574)] and center-based CR (mean [SE], €5507 [€659] [$6289 ($753)]; P = .36). From a societal perspective, CTR was associated with lower costs compared with center-based CR (mean [SE], €20 495 [€ 2751] [$23 405 ($3142)] vs €24 381 [€3613] [$27 843 ($4126)], respectively), although this difference was not statistically significant (−€3887 [−$4439]; P = .34). Conclusions and Relevance In this economic evaluation, a CTR intervention with relapse prevention was likely to be cost-effective compared with center-based CR, suggesting that CTR maybe used as an alternative intervention for the treatment of patients with coronary artery disease. These results add to the evidence base in favor of CTR and may increase the implementation of CTR interventions in clinical practice.

Background The COVID-19 pandemic has caused the relocation of huge financial resources to departments dedicated to infected patients, at the expense of those suffering from other pathologies. Aim To compare clinical features and outcomes in COVID-19 pneumonia and non-COVID-19 pneumonia patients. Patients and methods 53 patients (35 males, mean age 61.5 years) with COVID-19 pneumonia and 50 patients (32 males, mean age 72.7 years) with non-COVID-19 pneumonia, consecutively admitted between March and May 2020 were included. Clinical, laboratory and radiological data at admission were analyzed. Duration of hospitalization and mortality rates were evaluated. Results Among the non-COVID patients, mean age, presence of comorbidities (neurological diseases, chronic kidney disease and chronic obstructive pulmonary disease), Charlson Comorbidity Index and risk factors (tobacco use and protracted length of stay in geriatric healthcare facilities) were higher than in COVID patients. The non-COVID-19 pneumonia group showed a higher (24% vs. 17%), although not statistically significant in-hospital mortality rate; the average duration of hospitalization was longer for COVID patients (30 vs. 9 days, p = .0001). Conclusions In the early stages of the COVID pandemic, our centre noted no statistical difference in unadjusted in-hospital mortality between COVID and non-COVID patients. Non-COVID patients had higher Charlson Comorbidity Scores, reflecting a greater disease burden in this population. • Key Messages • In March 2020, the COVID-19 disease was declared a pandemic, with enormous consequences for the organization of health systems and in terms of human lives; this has caused the relocation of huge financial resources to departments dedicated to infected patients, at the expense of those suffering from other pathologies. • Few published reports have compared COVID-19 and non-COVID-19 pneumonia. In our study, performed in a geographic area with a low prevalence of SARS-CoV-2 infection, we found few statistically significant differences in terms of clinical characteristics between the two groups analyzed. • In the early stages of the COVID pandemic, our centre noted no statistical difference in unadjusted in-hospital mortality between COVID and non-COVID patients. Non-COVID patients had higher Charlson Comorbidity Scores, reflecting a greater disease burden in this population

Aim This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients. Methods A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. Structure Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated, and shared decision-making with patients is recommended.

Background: Cardiac magnetic resonance (CMR) pharmacological stress-testing is a well-established technique for detecting myocardial ischemia. Although stressors and contrast agents seem relatively safe, contraindications and side effects must be considered. Substantial costs are further limiting its applicability. Dynamic handgrip exercise (DHE) may have the potential to address these shortcomings as a physiological stressor. We therefore evaluated the feasibility and physiologic stress response of DHE in relation to pharmacological dobutamine-stimulation within the context of CMR examinations. Methods: Two groups were prospectively enrolled: (I) volunteers without relevant disease and (II) patients with known CAD referred for stress-testing. A both-handed, metronome-guided DHE was performed over 2 min continuously with 80 contractions/minute by all participants, whereas dobutamine stress-testing was only performed in group (II). Short axis strain by fast-Strain-ENCoded imaging was acquired at rest, immediately after DHE and during dobutamine infusion. Results: Eighty middle-aged individuals (age 56 ± 17 years, 48 men) were enrolled. DHE triggered significant positive chronotropic (HR rest : 68 ± 10 bpm, HR DHE : 91 ± 13 bpm, p < 0.001) and inotropic stress response (GLS rest : −19.4 ± 1.9%, GLS DHE : −20.6 ± 2.1%, p < 0.001). Exercise-induced increase of longitudinal strain was present in healthy volunteers and patients with CAD to the same extent, but in general more pronounced in the midventricular and apical layers ( p < 0.01). DHE was aborted by a minor portion (7%) due to peripheral fatigue. The inotropic effect of DHE appears to be non-inferior to intermediate dobutamine-stimulation (GLS DHE = −19.5 ± 2.3%, GLS Dob = −19.1 ± 3.1%, p = n.s.), whereas its chronotropic effect was superior (HR DHE = 89 ± 14 bpm, HR Dob = 78 ± 15 bpm, p < 0.001). Conclusions: DHE causes positive ino- and chronotropic effects superior to intermediate dobutamine-stimulation, suggesting a relevant increase of myocardial oxygen demand. DHE appears to be safe and timesaving with broad applicability. The data encourages further studies to determine its potential to detect obstructive CAD.

The drug-coated balloon (DCB) is an emerging percutaneous coronary intervention (PCI) device with theoretical advantages and promising results. Recent clinical observations have demonstrated that DCB tends to have both good efficacy and a good safety profile in the treatment of in-stent restenosis (ISR) for both bare-metal and drug-eluting stents (DES), de novo coronary artery disease (CAD), and other situation, such as high bleeding risk, chronic total occlusion, and acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) has become an essential medication in daily clinical practice, but the optimal duration of DAPT after the implantation of a DCB remains unknown. At the time of the first in vivo implantation of paclitaxel-DCB for the treatment of ISR in 2006, the protocol-defined DAPT duration was only 1 month. Subsequently, DAPT duration ranging from 1 to 12 months has been recommended by various trials. However, there have been no randomized controlled trials (RCTs) on the optimal duration of DAPT after DCB angioplasty. Current clinical guidelines normally recommend the duration of DAPT after DCB-only angioplasty based on data from RCTs on the optimal duration of DAPT after stenting. In this review, we summarized current clinical trials on DCB-only angioplasty for different types of CADs and their stipulated durations of DAPT, and compared their clinical results such as restenosis, target lesion revascularization (TLR) and stent thrombosis event. We hope this review can assist clinicians in making reasonable decisions about the duration of DAPT after DCB implantation.

Objective: To determine the association of perceived stress with coagulation function and their predictive values for clinical outcomes. Methods: This prospective cohort study derived from a cross-sectional study for investigating the psychological status of inpatients with suspicious coronary heart disease (CHD). In this study, the 10-item Perceived Stress Scale (PSS-10) as an optional questionnaire was used to assess the severity of perceived stress. Coagulation function tests, such as activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen were measured within 1 h after admission. Furthermore, 241 patients with CHD out of 705 consecutive inpatients were included in the analyses and followed with a median of 26 months for the clinical outcomes. Results: The patients in high perceived stress status (PSS-10 score > 16) were with shorter APTT (36.71 vs. 38.45 s, p = 0.009). Shortened APTT ( ≤ 35.0 s) correlated with higher PSS-10 score (14.67 vs. 11.22, p = 0.003). The association of APTT with depression or anxiety was not found. Multiple linear models adjusting for PT estimated that every single point increase in PSS-10 was relevant to approximately 0.13 s decrease in APTT ( p = 0.001) regardless of the type of CHD. APTT (every 5 s increase: hazard ratio ( HR ) 0.68 [0.47–0.99], p = 0.041) and perceived stress (every 5 points increase: HR 1.31 [1.09–1.58], p = 0.005) could predict the cardiovascular outcomes. However, both predictive values would decrease when they were simultaneously adjusted. After adjusting for the physical clinical features, the associated of perceived stress on cardiac ( HR 1.25 [1.04–1.51], p = 0.020) and composite clinical outcomes ( HR 1.24 [1.05–1.47], p = 0.011) persisted. Conclusions: For the patients with CHD, perceived stress strongly correlates with APTT. The activation of the intrinsic coagulation pathway is one of the mechanisms that high perceived stress causes cardiovascular events. This hints at an important role of the interaction of mental stress and coagulation function on cardiovascular prognosis. More attention needs to be paid to the patients with CHD with high perceived stress.

Background: Post-operative (POP) atrial fibrillation (AF) is frequent in patients who undergo cardiac surgery. However, its prognostic impact in the long term remains unclear. Methods: We followed 1386 patients who underwent cardiac surgery for an average of 10 ± 3 years. According to clinical history of AF before and after surgery, four subgroups were identified: (1) patients with no history of AF and without episodes of AF during the first 30 days after surgery (control or Group 1, n = 726), (2) patients with no history of AF before surgery in whom new-onset POP AF was detected during the first 30 days after surgery (new-onset POP AF or Group 2, n = 452), (3) patients with a history of paroxysmal/persistent AF before cardiac surgery (Group 3, n = 125, including 87 POP AF patients and 38 who did not develop POP AF), and (4) patients with permanent AF at the time of cardiac surgery (Group 4, n = 83). All-cause mortality was the primary outcome of the study. We tested the associations of potential determinants with all-cause mortality using univariable and multivariable statistical analyses. Results: Overall, 473 patients (34%) died during follow-up. After adjustment for multiple confounders, new-onset POP AF (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 0.90–1.89; p = 0.1609), history of paroxysmal/persistent AF before cardiac surgery (HR = 1.33, 95% CI: 0.71–2.49; p = 0.3736), and permanent AF (Group 4) (HR = 1.55, 95% CI 0.82–2.95; p = 0.1803) were not associated with a significantly increased risk of mortality when compared with Group 1 (patients with no history of AF and without episodes of AF during the first 30 days after surgery). In new-onset POP AF patients, oral anticoagulation was not associated with mortality (HR = 1.13, 95% CI: 0.83–1.54; p = 0.4299). Conclusions: In this cohort of patients who underwent different types of heart surgery, POP AF was not associated with an increased risk of mortality. In this setting, the role of long-term anticoagulation remains unclear.

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.

Mare Mechelinck

Liver cirrhosis has been associated with an increased risk of coronary artery disease and clinical complications following percutaneous coronary revascularization. The present study is based on the hypothesis that cirrhosis may influence intimal hyperplasia following PCI. Sera from 10 patients with alcoholic liver cirrhosis and 10 age-matched healthy controls were used to stimulate cultured human coronary artery smooth muscle cells (HCASMC) for 48 h. HCASMC proliferation, migration, gene expression and apoptosis were investigated. Serum concentrations of growth factors and markers of liver function were also determined in patients and healthy controls. Treatment of HCASMC with patient sera reduced cell proliferation and migration (p < 0.05 vs. healthy controls), whereas apoptosis was unaffected (p = 0.160). Expression of genes associated with a synthetic vascular smooth muscle cell phenotype was decreased in cells stimulated with serum from cirrhotic patients (RBP1, p = 0.001; SPP1, p = 0.003; KLF4, p = 0.004). Platelet-derived growth factor-BB serum concentrations were lower in patients (p = 0.001 vs. controls). The results suggest the presence of circulating factors in patients with alcoholic liver cirrhosis affecting coronary smooth muscle cell growth. These findings may have implications for clinical outcomes following percutaneous coronary revascularization in these patients.

Per O Svensson

Background Family history of atherosclerotic cardiovascular disease (ASCVD) is easily accessible and captures genetic cardiovascular risk, but its prognostic value in secondary prevention is unknown. Methods and Results We followed 25 615 patients registered in SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) from their 1‐year revisit after a first‐time myocardial infarction during 2005 to 2013, until December 31, 2018. Data on relatives, diagnoses and socioeconomics were extracted from national registers. The association between family history and recurrent ASCVD was studied with Cox proportional‐hazard regression, adjusting for risk factors and socioeconomics. A family history of ASCVD was defined as hospitalization due to myocardial infarction, angina with coronary revascularization, stroke, or cardiovascular death in ≥1 parent or full sibling, with early‐onset defined as disease‐onset before 55 years in men and 65 in women. The additional discriminatory value of family history to Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention was assessed with Harrell's C‐index difference and reclassification was studied with continuous net reclassification improvement. Family history of early‐onset ASCVD in ≥1 first‐degree relative was present in 2.3% and was associated with recurrent ASCVD (hazard ratio [HR] 1.31; 95% CI, 1.17–1.47), fully adjusted for risk factors (HR, 1.22; 95% CI, 1.05–1.42). Early‐onset family history improved the discriminatory ability of the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, with Harrell's C improving 0.003 points (95% CI, 0.001–0.005) from initial 0.587 (95% CI, 0.576–0.595) and improved reclassification (continuous net reclassification improvement 2.1%, P <0.001). Conclusions Family history of early‐onset ASCVD is associated with recurrent ASCVD after myocardial infarction, independently of traditional risk factors and improves secondary risk prediction. This may identify patients to target for intensified secondary prevention.

Aims The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes. Materials and methods CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored. Results A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m2. Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m2. The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria. Conclusions The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.

The Task Force on myocardial revascularization of the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association for Percutaneous Cardiovascular Interventions (EAPCI).

Aims The effect of first-line antianginal agents, β-blockers, and calcium antagonists on clinical outcomes in stable coronary artery disease (CAD) remains uncertain. Methods and results We analysed the use of β-blockers or calcium antagonists (baseline and annually) and outcomes in 22 006 stable CAD patients (enrolled 2009–2010) followed annually to 5 years, in the CLARIFY registry (45 countries). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death and the composite of cardiovascular death/non-fatal myocardial infarction (MI). After multivariable adjustment, baseline β-blocker use was not associated with lower all-cause death [1345 (7.8%) in users vs. 407 (8.4%) in non-users; hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84–1.06; P = 0.30]; cardiovascular death [861 (5.0%) vs. 262 (5.4%); HR 0.91, 95% CI 0.79–1.05; P = 0.20]; or cardiovascular death/non-fatal MI [1272 (7.4%) vs. 340 (7.0%); HR 1.03, 95% CI 0.91–1.16; P = 0.66]. Sensitivity analyses according to β-blocker use over time and to prescribed dose produced similar results. Among prior MI patients, for those enrolled in the year following MI, baseline β-blocker use was associated with lower all-cause death [205 (7.0%) vs. 59 (10.3%); HR 0.68, 95% CI 0.50–0.91; P = 0.01]; cardiovascular death [132 (4.5%) vs. 49 (8.5%); HR 0.52, 95% CI 0.37–0.73; P = 0.0001]; and cardiovascular death/non-fatal MI [212 (7.2%) vs. 59 (10.3%); HR 0.69, 95% CI 0.52–0.93; P = 0.01]. Calcium antagonists were not associated with any difference in mortality. Conclusion In this contemporary cohort of stable CAD, β-blocker use was associated with lower 5-year mortality only in patients enrolled in the year following MI. Use of calcium antagonists was not associated with superior mortality, regardless of history of MI.

Jacob Reeh
Christina Therming
Merete Heitmann
Eva Prescott

Aims: We hypothesized that the modified Diamond-Forrester (D-F) prediction model overestimates probability of coronary artery disease (CAD). The aim of this study was to update the prediction model based on pre-test information and assess the model's performance in predicting prognosis in an unselected, contemporary population suspected of angina. Methods and results: We included 3903 consecutive patients free of CAD and heart failure and suspected of angina, who were referred to a single centre for assessment in 2012-15. Obstructive CAD was defined from invasive angiography as lesion requiring revascularization, >70% stenosis or fractional flow reserve <0.8. Patients were followed (mean follow-up 33 months) for myocardial infarction, unstable angina, heart failure, stroke, and death. The updated D-F prediction model overestimated probability considerably: mean pre-test probability was 31.4%, while only 274 (7%) were diagnosed with obstructive CAD. A basic prediction model with age, gender, and symptoms demonstrated good discrimination with C-statistics of 0.86 (95% CI 0.84-0.88), while a clinical prediction model adding diabetes, family history, and dyslipidaemia slightly improved the C-statistic to 0.88 (0.86-0.90) (P for difference between models <0.0001). Quartiles of probability of CAD from the clinical prediction model provided good diagnostic and prognostic stratification: in the lowest quartiles there were no cases of obstructive CAD and cumulative risk of the composite endpoint was less than 3% at 2 years. Conclusion: The pre-test probability model recommended in current ESC guidelines substantially overestimates likelihood of CAD when applied to a contemporary, unselected, all-comer population. We provide an updated prediction model that identifies subgroups with low likelihood of obstructive CAD and good prognosis in which non-invasive testing may safely be deferred.

Aims To provide a pooled estimation of contemporary pre-test probabilities (PTPs) of significant coronary artery disease (CAD) across clinical patient categories, re-evaluate the utility of the application of diagnostic techniques according to such estimates, and propose a comprehensive diagnostic technique selection tool for suspected CAD. Methods and results Estimates of significant CAD prevalence across sex, age, and type of chest pain categories from three large-scale studies were pooled (n = 15 815). The updated PTPs and diagnostic performance profiles of exercise electrocardiogram, invasive coronary angiography, coronary computed tomography angiography (CCTA), positron emission tomography (PET), stress cardiac magnetic resonance (CMR), and SPECT were integrated to define the PTP ranges in which ruling-out CAD is possible with a post-test probability of <10% and <5%. These ranges were then integrated in a new colour-coded tabular diagnostic technique selection tool. The Bayesian relationship between PTP and the rate of diagnostic false positives was explored to complement the characterization of their utility. Pooled CAD prevalence was 14.9% (range = 1–52), clearly lower than that used in current clinical guidelines. Ruling-out capabilities of non-invasive imaging were good overall. The greatest ruling-out capacity (i.e. post-test probability <5%) was documented by CCTA, PET, and stress CMR. With decreasing PTP, the fraction of false positive findings rapidly increased, although a lower CAD prevalence partially cancels out such effect. Conclusion The contemporary PTP of significant CAD across symptomatic patient categories is substantially lower than currently assumed. With a low prevalence of the disease, non-invasive testing can rarely rule-in the disease and focus should shift to ruling-out obstructive CAD. The large proportion of false positive findings must be taken into account when patients with low PTP are investigated.

Renato D Lopes
Gretchen Heizer
Ronald Aronson
John H Alexander

Background Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. Methods In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. Results Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P=0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. Conclusions In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.)

Background E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments. Methods We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a second-generation refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms. Results A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath. Conclusions E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support. (Funded by the National Institute for Health Research and Cancer Research UK; Current Controlled Trials number, ISRCTN60477608.)

Source: https://www.researchgate.net/publication/335525686_2019_ESC_Guidelines_for_the_diagnosis_and_management_of_chronic_coronary_syndromes

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