2013ESC稳定型冠心病诊疗指南

ESC GUIDELINES 2013ESC guidelines on the management

of stable coronary artery disease

The Task Force on the management of stable coronary artery disease of the European Society of Cardiology

Task Force Members:Gilles Montalescot *(Chairperson)(France),Udo Sechtem *(Chairperson)(Germany),Stephan Achenbach (Germany),Felicita Andreotti (Italy),Chris Arden (UK),Andrzej Budaj (Poland),Raffaele Bugiardini (Italy),Filippo Crea (Italy),Thomas Cuisset (France),Carlo Di Mario (UK),J.Rafael Ferreira (Portugal),Bernard J.Gersh (USA),Anselm K.Gitt (Germany),Jean-Sebastien Hulot (France),Nikolaus Marx (Germany),Lionel H.Opie (South Africa),Matthias P?sterer

(Switzerland),Eva Prescott (Denmark),Frank Ruschitzka (Switzerland),Manel Sabate ′(Spain),Roxy Senior (UK),David Paul Taggart (UK),Ernst E.van der Wall

(Netherlands),Christiaan J.M.Vrints (Belgium).

ESC Committee for Practice Guidelines (CPG):Jose Luis Zamorano (Chairperson)(Spain),Stephan Achenbach (Germany),Helmut Baumgartner (Germany),Jeroen J.Bax (Netherlands),He ′ctor Bueno (Spain),Veronica Dean (France),Christi Deaton (UK),Cetin Erol (Turkey),Robert Fagard (Belgium),Roberto Ferrari (Italy),David Hasdai (Israel),Arno W.Hoes (Netherlands),Paulus Kirchhof (Germany/UK),Juhani Knuuti (Finland),Philippe Kolh (Belgium),Patrizio Lancellotti (Belgium),Ales Linhart (Czech Republic),Petros Nihoyannopoulos (UK),Massimo F.Piepoli (Italy),Piotr Ponikowski (Poland),Per Anton Sirnes (Norway),Juan Luis Tamargo (Spain),Michal Tendera (Poland),Adam Torbicki (Poland),William Wijns (Belgium),Stephan Windecker (Switzerland).

Document Reviewers:Juhani Knuuti (CPG Review Coordinator)(Finland),Marco Valgimigli (Review Coordinator)(Italy),He ′ctor Bueno (Spain),Marc J.Claeys (Belgium),Norbert Donner-Banzhoff (Germany),Cetin Erol (Turkey),Herbert Frank (Austria),Christian Funck-Brentano (France),Oliver Gaemperli (Switzerland),

Jose ′R.Gonzalez-Juanatey (Spain),Michalis Hamilos (Greece),David Hasdai (Israel),Steen Husted (Denmark),Stefan K.James (Sweden),Kari Kervinen (Finland),Philippe Kolh (Belgium),Steen Dalby Kristensen (Denmark),Patrizio Lancellotti (Belgium),Aldo Pietro Maggioni (Italy),Massimo F.Piepoli (Italy),Axel R.Pries

(Germany),*Corresponding authors.The two chairmen contributed equally to the documents.Chairman,France:Professor Gilles Montalescot,Institut de Cardiologie,Pitie-Salpetriere University Hospital,Bureau 2-236,47-83Boulevard de l’Hopital,75013Paris,France.Tel:+33142163006,Fax:+33142162931.Email:gilles.montalescot@psl.aphp.fr .Chairman,Germany:Professor Udo Sechtem,Abteilung fu ¨r Kardiologie,Robert Bosch Krankenhaus,Auerbachstr.110,DE-70376Stuttgart,Germany.Tel:+4971181013456,Fax:+4971181013795,Email:udo.sechtem@rbk.de

Entities having participated in the development of this document:

ESC Associations:Acute Cardiovascular Care Association (ACCA),European Association of Cardiovascular Imaging (EACVI),European Association for Cardiovascular Prevention &Rehabilitation (EACPR),European Association of Percutaneous Cardiovascular Interventions (EAPCI),Heart Failure Association (HFA)

ESC Working Groups:Cardiovascular Pharmacology and Drug Therapy,Cardiovascular Surgery,Coronary Pathophysiology and Microcirculation,Nuclear Cardiology and Cardiac CT,Thrombosis,Cardiovascular Magnetic Resonance

ESC Councils:Cardiology Practice,Primary Cardiovascular Care

The content of these European Society of Cardiology (ESC)Guidelines has been published for personal and educational use only.No commercial use is authorized.No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC.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.

Disclaimer .The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health profes-sionals are encouraged to take them fully into account when exercising their clinical judgement.The Guidelines do not,however,override the individual responsibility of health profes-sionals to make appropriate decisions in the circumstances of the individual patients,in consultation with that patient and where appropriate and necessary the patient’s guardian or carer.It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

&The European Society of Cardiology 2013.All rights reserved.For permissions please email:journals.permissions@929cf97c5022aaea998f0fc9 European Heart Journal doi:10.1093/eurheartj/eht296

European Heart Journal Advance Access published August 30, 2013 by guest on September 3, 2013929cf97c5022aaea998f0fc9/Downloaded from

Francesco Romeo (Italy),Lars Ryde

′n (Sweden),Maarten L.Simoons (Netherlands),Per Anton Sirnes (Norway),Ph.Gabriel Steg (France),Adam Timmis (UK),William Wijns (Belgium),Stephan Windecker (Switzerland),Aylin Yildirir (Turkey),Jose Luis Zamorano (Spain).

The disclosure forms of the authors and reviewers are available on the ESC website 929cf97c5022aaea998f0fc9/guidelines

------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Guidelines ?Angina pectoris ?Myocardial ischaemia ?Stable coronary artery disease ?Risk factors ?anti-ischaemic drugs ?Coronary revascularization

Table of Contents

1.Preamble ...................................6

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

3.De?nitions and pathophysiology (see web addenda).......7

4.Epidemiology ................................8

5.Natural history and prognosis ......................8

6.

Diagnosis and assessment (see web addenda)............96.1Symptoms and signs (see web addenda)............96.2Non-invasive cardiac investigations ...............106.2.1Basic testing...........................106.2.1.1Biochemical tests (see web addenda).........106.2.1.2Resting electrocardiogram ................126.2.1.3Echocardiography at rest (see web addenda)....126.2.1.4Cardiac magnetic resonance at rest...........126.2.1.5Ambulatory electrocardiogram monitoring......136.2.1.6Chest X-ray .........................136.2.2Three major steps used for decision-making ......136.2.3Principles of diagnostic testing ...............136.2.4Stress testing for diagnosing ischaemia ..........156.2.4.1Electrocardiogram exercise testing ...........156.2.4.2Stress imaging (see web addenda)............176.2.4.2.1Stress echocardiography .. (17)

6.2.4.2.2Myocardial perfusion scintigraphy (single photon emission computed tomography and positron emission tomography)......................186.2.4.2.3Stress cardiac magnetic resonance ........186.2.4.2.4Hybrid techniques ..................186.2.5Non-invasive techniques to assess coronary anatomy 186.2.5.1Computed tomography ..................186.2.5.1.1Calcium scoring ....................186.2.5.1.2Coronary computed tomography angiography 186.2.5.2Magnetic resonance coronary angiography ......196.3Invasive coronary angiography (see web addenda).....196.4Strati?cation for risk of events (see web addenda).....206.4.1Event risk strati?cation using clinical evaluation ....216.4.2Event risk strati?cation using ventricular function ...216.4.3Event risk strati?cation using stress testing .......226.4.3.1Electrocardiogram stress testing.............226.4.3.2Stress echocardiography .................226.4.3.3Stress perfusion scintigraphy (single photon emission computed tomography and positron emission tomography).236.4.3.4Stress cardiac magnetic resonance ...........

23

6.4.4Event risk strati?cation using coronary anatomy ....236.4.4.1Coronary computed tomography angiography ...236.4.4.2Invasive coronary angiography ..............236.5Diagnostic aspects in the asymptomatic individual without known coronary artery disease (see web addenda).......246.6Management aspects in the patient with known coronary artery disease ...............................256.7Special diagnostic considerations:angina with ‘normal’coronary arteries (see web addenda)................256.

7.1Microvascular angina .....................266.7.1.1Clinical picture (see web addenda)...........266.7.1.2Pathogenesis and prognosis (see web addenda)...266.7.1.3Diagnosis and management of coronary

microvascular disease (see web addenda)............266.7.2Vasospastic angina.......................266.7.2.1Clinical picture ........................266.7.2.2Pathogenesis and prognosis (see web addenda )..266.7.2.3Diagnosis of vasospastic angina .............266.7.2.3.1Electrocardiography .................266.7.2.3.2Coronary arteriography ...............

277.Lifestyle and pharmacological management .............

277.1Risk factors and ischaemia management ............277.1.1General management of stable coronary artery disease patients .................................277.1.2Lifestyle modi?cations and control of risk factors ...277.1.2.1Smoking ............................277.1.2.2Diet (Table 25)........................277.1.2.3Physical activity .......................287.1.2.4Sexual activity ........................287.1.2.5Weight management ....................287.1.2.6Lipid management......................287.1.2.7Arterial Hypertension ...................287.1.2.8Diabetes and other disorders ..............297.1.2.9Psychosocial factors ....................297.1.2.10Cardiac rehabilitation...................297.1.2.11In?uenza vaccination ...................297.1.2.12Hormone replacement therapy ............297.1.3Pharmacological management of stable coronary artery disease patients ........................297.1.3.1Aims of treatment......................297.1.3.2Drugs .............................

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7.1.3.3Anti-ischaemic drugs ....................307.1.3.3.1Nitrates .........................307.1.3.3.2b -Blockers .......................307.1.3.3.3Calcium channel blockers ..............307.1.3.3.4Ivabradine ........................337.1.3.3.5Nicorandil .......................337.1.3.3.6Trimetazidine .....................337.1.3.3.7Ranolazine .......................337.1.3.3.8Allopurinol .......................337.1.3.3.9Molsidomine ......................337.1.3.4Patients with low blood pressure ............337.1.3.5Patients with low heart rate ...............337.2Event prevention ..........................347.2.1Antiplatelet agents ......................347.2.1.1Low-dose aspirin ......................347.2.1.2P2Y12inhibitors.......................347.2.1.3Combination of antiplatelet agents ...........347.2.1.4Poor response to antiplatelet agents ..........347.2.2Lipid-lowering agents (see lipid management,above).347.2.3Renin-angiotensin-aldosterone system blockers ....347.3Other drugs .............................357.3.1Analgesics ............................357.4Strategy ................................357.5Treatment of particular forms of SCAD ............357.5.1Microvascular angina .....................357.5.2Treatment of vasospastic angina ..............368.Revascularization ..............................

368.1Percutaneous coronary intervention ..............368.1.1Type of stent and dual antiplatelet therapy . (36)

8.1.2Intracoronary assessment of stenosis severity

(fractional ?ow reserve,intravascular ultrasound and optical coherence tomography)(see web addenda)..........378.2Coronary artery bypass surgery .................388.2.1Arterial vs.venous grafts...................388.2.2On-pump vs.off-pump surgery (see web addenda)..398.3Revascularization vs.medical therapy .............398.3.1General rules for revascularization (see web addenda)398.3.1.1Post-myocardial infarction ................398.3.1.2Left ventricular dysfunction ................408.3.1.3Multivessel disease and/or large ischaemic territory 408.3.1.4Left main coronary artery disease ............418.3.2Revascularization in lower-risk populations .......418.3.2.1The randomized studies (see web addenda).....418.3.2.2Limitations of the randomized studies (see web addenda)................................438.3.2.3Overall interpretation ...................438.3.2.4Ongoing studies for management of stable

coronary artery disease patients with demonstrated ischaemia .438.4Percutaneous coronary intervention vs.coronary artery bypass graft (see web addenda)....................438.4.1Recent data and recommendations ............438.4.2Target populations of the randomized studies (see web addenda).............................458.5Scores and decisions (see web addenda)...........458.5.1Scores (see web addenda).................458.5.2Appropriate utilization of revascularization (see web addenda)................................

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9.Special groups or considerations ....................

469.1Women (see web addenda)...................469.2Patients with diabetes (see web addenda)...........469.3Patients with chronic kidney disease (see web addenda).469.4Elderly patients (see web addenda)...............469.5The patient after revascularization (see web addenda)...469.6Repeat revascularization of the patient with prior coronary artery bypass graft revascularization (see web addenda)....479.7Chronic total occlusions (see web addenda).........479.8Refractory angina (see web addenda).............479.9Primary care (see web addenda)................489.10Gaps in evidence (see web addenda).............48References ....................................

48

List of tables

Table 1Classes of recommendations ..........................6Table 2Levels of evidence ....................................7Table 3Main features of stable coronary artery disease..........8Table 4Traditional clinical classi?cation of chest pain............9Table 5Classi?cation of angina severity according to the

Canadian Cardiovascular Society ..........................10Table 6Traditional clinical classi?cation of chest pain...........11Table 7Blood tests for routine re-assessment in patients with

chronic stable coronary artery disease......................11Table 8Resting electrocardiogram for initial diagnostic

assessment of stable coronary artery disease................12Table 9Echocardiography ...................................12Table 10Ambulatory electrocardiogram monitoring for initial

diagnostic assessment of stable coronary artery disease......13Table 11Chest X-ray for initial diagnostic assessment of

stable coronary artery disease.............................13Table 12Characteristics of tests commonly used to diagnose

the presence of coronary artery disease.....................14Table 13Clinical pre-test probabilities in patients with stable

chest pain symptoms .....................................14Table 14Performing an exercise electrocardiogram for initial diagnostic assessment of angina or evaluation of

symptoms ...............................................17Table 15Use of exercise or pharmacologic stress

testing in combination with imaging ........................17Table 16The use of coronary computed tomography angiography for the diagnosis of stable coronary artery

disease ..................................................19Table 17De?nitions of risk for various test modalities..........20Table 18Risk strati?cation by resting echocardiography quanti?cation of ventricular function in stable coronary

artery disease............................................22Table 19Risk strati?cation using ischaemia testing..............22Table 20Risk strati?cation by invasive or non-invasive coronary arteriography in patients with stable coronary

artery disease............................................24Table 21Testing in asymptomatic patients at risk for stable

coronary artery disease...................................24Table 22Re-assessment in patients with stable coronary

artery disease (25)

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microvascular disease (26)

Table24Diagnostic tests in suspected vasospastic angina (27)

Table25Recommended diet intakes (28)

Table26Blood pressure thresholds for de?nition of

hypertension with different types of blood pressure

measurement (29)

Table27Major side-effects,contra-indications,drug–drug interactions and precautions of anti-ischaemic drug (31)

Table28Pharmacological treatments in stable coronary artery disease patients (32)

Table29Treatment in patients with microvascular angina (36)

Table30Stenting and peri-procedural antiplatelet strategies in stable coronary artery disease patients (37)

Table31Use of fractional?ow reserve,intravascular

ultrasound,and optical coherence tomography in stable

coronary artery disease (38)

Table32Indications for revascularization of stable coronary artery disease patients on optimal medical therapy(adapted

from ESC/EACTS2010Guidelines) (41)

Table33Characteristics of the seven more recent

randomized trials (42)

Table34Follow-up of revascularized stable coronary artery disease patients (47)

Table35Treatment options in refractory angina (48)

List of?gures

Figure1Initial diagnostic management (15)

Figure2Non-invasive testing in patients with intermediate pre-test probability (16)

Figure3Management based on risk-determination (21)

Figure4Medical management of patients with stable coronary artery disease (35)

Figure5Global strategy of intervention in stable coronary artery disease patients with demonstrated ischaemia (40)

Figure6Percutaneous coronary intervention or coronary artery bypass graft surgery in stable coronary artery disease without left main coronary artery involvement (44)

Figure7Percutaneous coronary intervention or coronary artery bypass graft surgery in stable coronary artery disease with left main coronary artery involvement (45)

Abbreviations and acronyms

99m Tc technetium-99m

201TI thallium201

ABCB1ATP-binding cassette sub-family B member1 ABI ankle-brachial index

ACC American College of Cardiology

ACCF American College of Cardiology Foundation

ation Therapy in Patients Living With Systolic

Hypertension

ACE angiotensin converting enzyme

ACIP Asymptomatic Cardiac Ischaemia Pilot

ACS acute coronary syndrome

ADA American Diabetes Association

ADP adenosine diphosphate

AHA American Heart Association

ARB angiotensin II receptor antagonist

ART Arterial Revascularization Trial

ASCOT Anglo-Scandinavian Cardiac Outcomes Trial

ASSERT Asymptomatic atrial?brillation and Stroke Evalu-

ation in pacemaker patients and the atrial?brilla-

tion Reduction atrial pacing Trial

AV atrioventricular

BARI2D Bypass Angioplasty Revascularization Investigation

2Diabetes

BEAUTIFUL Morbidity-Mortality Evaluation of the I f Inhibitor

Ivabradine in Patients With Coronary Artery

Disease and Left Ventricular Dysfunction

BIMA bilateral internal mammary artery

BMI body mass index

BMS bare metal stent

BNP B-type natriuretic peptide

BP blood pressure

b.p.m.beats per minute

CABG coronary artery bypass graft

CAD coronary artery disease

CAPRIE Clopidogrel vs.Aspirin in Patients at Risk of Ischae-

mic Events

CASS Coronary Artery Surgery Study

CCB calcium channel blocker

CCS Canadian Cardiovascular Society

CFR coronary?ow reserve

CHARISMA Clopidogrel for High Atherothrombotic Risk and

Ischaemic Stabilization,Management and Avoid-

ance

CI con?dence interval

CKD chronic kidney disease

CKD-EPI Chronic Kidney Disease Epidemiology Collabor-

ation

CMR cardiac magnetic resonance

CORONARY The CABG Off or On Pump Revascularization Study COURAGE Clinical Outcomes Utilizing Revascularization and

Aggressive Drug Evaluation

COX-1cyclooxygenase-1

COX-2cyclooxygenase-2

CPG Committee for Practice Guidelines

CT computed tomography

CTA computed tomography angiography

CV cardiovascular

CVD cardiovascular disease

CXR chest X-ray

CYP2C19*2cytochrome P4502C19

CYP3A cytochrome P3A

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CYP450cytochrome P450

DANAMI Danish trial in Acute Myocardial Infarction DAPT dual antiplatelet therapy

DBP diastolic blood pressure

DECOPI Desobstruction Coronaire en Post-Infarctus DES drug-eluting stents

DHP dihydropyridine

DSE dobutamine stress echocardiography

EACTS European Association for Cardiothoracic Surgery EECP enhanced external counterpulsation

EMA European Medicines Agency

EASD European Association for the Study of Diabetes ECG electrocardiogram

Echo echocardiogram

ED erectile dysfunction

EF ejection fraction

ESC European Society of Cardiology

EXCEL Evaluation of XIENCE PRIME or XIENCE V vs.

Coronary Artery Bypass Surgery for Effectiveness

of Left Main Revascularization

FAME Fractional Flow Reserve vs.Angiography for Multi-

vessel Evaluation

FDA Food&Drug Administration(USA)

FFR fractional?ow reserve

FREEDOM Design of the Future Revascularization Evaluation

in patients with Diabetes mellitus:Optimal man-

agement of Multivessel disease

GFR glomerular?ltration rate

HbA1c glycated haemoglobin

HDL high density lipoprotein

HDL-C high density lipoprotein cholesterol

HR hazard ratio

HRT hormone replacement therapy

hs-CRP high-sensitivity C-reactive protein

HU Houns?eld units

ICA invasive coronary angiography

IMA internal mammary artery

IONA Impact Of Nicorandil in Angina

ISCHEMIA International Study of Comparative Health Effect-

iveness with Medical and Invasive Approaches IVUS intravascular ultrasound

JSAP Japanese Stable Angina Pectoris

KATP ATP-sensitive potassium channels

LAD left anterior descending

LBBB left bundle branch block

LIMA Left internal mammary artery

LDL low density lipoprotein

LDL-C low density lipoprotein cholesterol

LM left main

LMS left main stem

LV left ventricular

LVEF left ventricular ejection fraction

LVH left ventricular hypertrophy

MACE major adverse cardiac events MDRD Modi?cation of Diet in Renal Disease

MERLIN Metabolic Ef?ciency with Ranolazine for Less

Ischaemia in Non-ST-Elevation Acute Coronary

Syndromes

MERLIN-TIMI

36

Metabolic Ef?ciency with Ranolazine for Less Is-

chemia in Non-ST-Elevation Acute Coronary Syn-

dromes:Thrombolysis In Myocardial Infarction

MET metabolic equivalents

MI myocardial infarction

MICRO-HOPE Microalbuminuria,cardiovascular and renal sub-

study of the Heart Outcomes Prevention Evalu-

ation study

MPI myocardial perfusion imaging

MRI magnetic resonance imaging

NO nitric oxide

NSAIDs non-steroidal anti-in?ammatory drugs

NSTE-ACS non-ST-elevation acute coronary syndrome

NYHA New York Heart Association

OAT Occluded Artery Trial

OCT optical coherence tomography

OMT optimal medical therapy

PAR-1protease activated receptor type1

PCI percutaneous coronary intervention

PDE5phosphodiesterase type5

PES paclitaxel-eluting stents

PET positron emission tomography

PRECOMBAT Premier of Randomized Comparison of Bypass

Surgery vs.Angioplasty Using Sirolimus-Eluting

Stent in Patients with Left Main Coronary Artery

Disease

PTP pre-test probability

PUFA polyunsaturated fatty acid

PVD peripheral vascular disease

QoL quality of life

RBBB right bundle branch block

REACH Reduction of Atherothrombosis for Continued

Health

RITA-2Second Randomized Intervention Treatment of

Angina

ROOBY Veterans Affairs Randomized On/Off Bypass

SAPT single antiplatelet therapy

SBP systolic blood pressure

SCAD stable coronary artery disease

SCORE Systematic Coronary Risk Evaluation

SCS spinal cord stimulation

SES sirolimus-eluting stents

SIMA single internal mammary artery

SPECT single photon emission computed tomography

STICH Surgical Treatment for Ischaemic Heart Failure

SWISSI II Swiss Interventional Study on Silent Ischaemia

Type II

SYNTAX SYNergy between percutaneous coronary inter-

vention with TAXus and cardiac surgery

TC total cholesterol

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TENS transcutaneous electrical neural stimulation TERISA Type 2Diabetes Evaluation of Ranolazine in Sub-jects With Chronic Stable Angina TIME Trial of Invasive vs.Medical therapy TIMI Thrombolysis In Myocardial Infarction TMR transmyocardial laser revascularization TOAT The Open Artery Trial WOEST What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing 1.Preamble Guidelines summarize and evaluate all evidence available,at the time of the writing process,on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individ-ual patient with a given condition,taking into account the impact on outcome,as well as the risk–bene?t ratio of particular diagnostic or therapeutic means.Guidelines are not substitutes but are complements for textbooks,and cover the ESC Core Curriculum topics.Guidelines and recommendations should help physicians to make decisions in their daily practice:however,the ?nal decisions concerning an individual patient must be made by the responsible physician(s).A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC)as well as by other societies and organisations.Because of the impact on clinical prac-tice,quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user.The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (929cf97c5022aaea998f0fc9/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx ).ESC Guidelines represent the of?cial position of the ESC on a given topic and are regularly updated.Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this

pathology.Selected experts in the ?eld undertook a comprehensive

review of the published evidence for the diagnosis,management and/or prevention of a given condition according to the ESC Committee for Practice Guidelines (CPG)policy.A critical evaluation of diagnos-tic and therapeutic procedures was performed,including assessment of the risk–bene?t ratio.Estimates of expected health outcomes for

larger populations were included,where data exist.The level of evi-dence and the strength of recommendation of particular treatment

options were weighed and graded according to prede?ned scales,

as outlined in Tables 1and 2.

The experts of thewriting and reviewing panels completed Declar-

ation of Interest forms where real or potential sources of con?icts of

interest might be perceived.These forms were compiled into one ?le and can be found on the ESC website (929cf97c5022aaea998f0fc9/guidelines ).Any changes in declarations of interest that arise during the writing period must be noti?ed to the ESC and updated.The Task Force received its entire ?nancial support from the ESC,without any involvement from healthcare industry.The ESC CPG supervises and co-ordinates the preparation of new Guidelines produced by Task Forces,expert groups or consensus panels.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,they are approved by all the experts involved in the Task Force.The ?nalized document is approved by the CPG for publication in the European Heart Journal .The task of developing ESC Guidelines covers not only the integra-tion of the most recent research,but also the creation of educational tools and implementation programmes for the recommendations.To implement the guidelines,condensed pocket editions,summary slides,booklets with essential messages,electronic versions for digital applications (smartphones etc.)are produced.These versions are abridged and thus,if needed,one should always refer to the full ESC Guidelines Page 6of 62 by guest on September 3, 2013929cf97c5022aaea998f0fc9/Downloaded from

text version,which is freely available on the ESC website.The Nation-al Societies of the ESC are encouraged to endorse,translate and im-plement the ESC Guidelines.Implementation programmes are needed because it has been shown that the outcome of disease may be favourably in?uenced by the thorough application of clinical recommendations.Surveys and registries are needed to verify that real-life daily prac-tice is in keeping with what is recommended in the guidelines,thus completing the loop between clinical research,writing of guidelines and implementing them into clinical practice.

The Guidelines do not,however,override the individual responsi-bility of health professionals to make appropriate decisions in the cir-cumstances of the individual patient,in consultation with that patient and,where appropriate and necessary,the patient’s guardian or carer.It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.2.Introduction These guidelines should be applied to patients with stable known or suspected coronary artery disease (SCAD).This condition encom-passes several groups of patients:(i)those having stable angina pec-toris or other symptoms felt to be related to coronary artery disease (CAD)such as dyspnoea;(ii)those previously symptomatic with known obstructive or non-obstructive CAD,who have become asymptomatic with treatment and need regular follow-up;(iii)those who report symptoms for the ?rst time and are judged to already be in a chronic stable condition (for instance because history-taking reveals that similar symptoms were already present for several months).Hence,SCAD de?nes the different evolutionary phases of CAD,excluding the situations in,which coronary artery thrombosis dominates clinical presentation (acute coronary syn-dromes).However,patients who have a ?rst or recurrent manifestation of angina but can be categorized as having a low-risk acute coronary syn-drome (ACS)according to the current ACS guidelines of the ESC [no recurrence of chest pain,no signs of heart failure,no abnormalities in the resting electrocardiogram (ECG),no rise in markers of myocar-dial necrosis (preferably troponin)and hence are not candidates for swift intervention]1should also be managed according to the algo-rithms presented in these Guidelines.Although routine screening of asymptomatic patients is discouraged,2these guidelines can also

probability (PTP)of disease strongly in?uencing the diagnostic algo-rithms and they take into account recent advances in technology,the importance of physiological assessment of CAD in the catheteriza-tion laboratory and the increasing evidence that the prognostic bene?t of revascularization may be less than has been traditionally expected.In order to limit the length of the printed text,additional informa-tion,tables,?gures and references are available as web addenda at the ESC website (929cf97c5022aaea998f0fc9 ).3.De?nitions and pathophysiology (see web addenda)Stable coronary artery disease is generally characterized by episodes of reversible myocardial demand/supply mismatch,related to ischae-mia or hypoxia,which are usually inducible by exercise,emotion or

other stress and reproducible—but,which may also be occurring spontaneously.Such episodes of ischaemia/hypoxia are commonly

associated with transient chest discomfort (angina pectoris).SCAD

also includes the stabilized,often asymptomatic,phases that follow

an ACS.Because the transition from unstable to stable syndromes is a con-tinuum,without a clear boundary,angina at rest caused by coronary vasospasm may be regarded within the scope of SCAD,3–5as in the present document or,conversely,within the scope of ACS as in some,6but not in other,1ACS guidelines.Recent use of ultrasensitive troponin tests has shown that episodes of minute troponin release—below the threshold for acute myocardial infarction—often occur in patients with stable CAD and this has been shown to have prognostic implications,7,8,9thus also demonstrating the continuum of CAD sub-groups.The various clinical presentations of SCAD (see also section 6.1)are associated with different underlying mechanisms that mainly include:(i)plaque-related obstruction of epicardial arteries;(ii)focal or diffuse spasm of normal or plaque-diseased arteries;(iii)microvascular dysfunction and (iv)left ventricular dysfunction caused by prior acute myocardial necrosis and/or hibernation (is-chaemic cardiomyopathy)(Table 3).These mechanisms may act singly or in combination.However,stable coronary plaques with and without previous revascularization may also be completely clin-ically silent.Additional information on the relationship between symptoms and underlying disease mechanisms,the histology of epi-cardial lesions,the de?nitions and pathogenesis of vasospasm,the by guest on September 3, 2013929cf97c5022aaea998f0fc9/Downloaded from

de?nition of microvascular dysfunction and ischaemic cardiomyop-athy is available in sections 3.1–3.5of the web addenda.

Myocardial ischaemia and hypoxia in SCAD are caused by a tran-sient imbalance between blood supply and metabolic demand.The consequences of ischaemia occur in a predictable temporal sequence that involves:

(1)Increased H +and K +concentration in the venous blood that

drains the ischaemic territory

(2)Signs of ventricular diastolic and subsequently systolic dysfunc-tion with regional wall motion abnormalities (3)Development of ST–T changes (4)Cardiac ischaemic pain (angina).10

This sequence explains why imaging techniques based on perfusion,metabolism or wall motion are more sensitive than an ECG or symp-toms in detecting ischaemia.Angina is ultimately caused by the release of ischaemic metabolites—such as adenosine—that stimu-late sensitive nerve endings,although angina may be absent even with severe ischaemia owing,for instance,to impaired transmission of painful stimuli to the cortex and other as-yet-unde?ned potential mechanisms.11

The functional severity of coronary lesions can be assessed by measuring coronary ?ow reserve (CFR)and intracoronary artery

diagnostic tools may additionally contribute to the contemporary high prevalence of diagnosed CAD.

Epidemiological data on microvascular angina and vasospastic angina are missing.However,recent clinical data suggest that abnor-mal coronary vasomotion is present in two-thirds of patients who suffer from stable angina but have no coronary stenoses at angiog-raphy.19

5.Natural history and prognosis

In many patients,early manifestations of CAD are endothelial dys-function and microvascular disease.Both are associated with an increased risk of complications from CAD.20–22

Contemporary data regarding prognosis can be derived from clin-ical trials of anti-anginal and preventive therapy and/or revasculariza-tion,although these data are biased by the selected nature of the populations studied.From these,estimates for annual mortality rates range from 1.2–2.4%per annum,23–28with an annual incidence of cardiac death between 0.6and 1.4%and of non-fatal myocardial in-farction (MI)between 0.6%in the Second Randomized Intervention Treatment of Angina (RITA-2)26and 2.7%in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)trials.23These estimates are consistent with observa-tional registry data.13,29

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However,within the population with stable CAD,an individual’s prognosis can vary considerably,depending on baseline clinical,func-tional and anatomical characteristics.This is exempli?ed in the Re-duction of Atherothrombosis for Continued Health (REACH)registry,30,which included very high-risk patients,many with periph-eral arterial disease or previous MI and almost 50%with diabetes.Consequently,annual mortality rate was as high as 3.8%in this popu-lation 30,whereas patients with non-obstructive plaques within the coronary arteries have an annual mortality rate of only 0.63%.

Prognostic assessment is an important part of the management of patients with SCAD.On the one hand,it is important to reliably iden-tify those patients with more severe forms of disease,who may have an improvement in outcome with more aggressive investigation and—potentially—intervention,including revascularization.On the other hand,it is also important to identify those patients with a less-severe form of disease and a good prognosis,thereby avoiding un-necessary invasive and non-invasive tests and revascularization pro-cedures.

Conventional risk factors for the development of CAD 31–33—hypertension,34hypercholesterolaemia,35diabetes,36sedentary life-style,37,obesity,37smoking,34,38and a family history 39—have an adverse in?uence on prognosis in those with established disease,pre-sumably through their effect on the progression of atherosclerotic disease processes.However,appropriate treatment can reduce these risks.40–42An elevated resting heart rate is also indicative of a worse prognosis in those with suspected or proven CAD.43In general,the outcome is worse in patients with reduced left ventricu-lar ejection fraction (LVEF)and heart failure,a greater number of dis-eased vessels,more proximal locations of coronary stenoses,greater severity of lesions,more extensive ischaemia,more impaired func-tional capacity,older age,signi?cant depression and more severe angina.44–47

6.Diagnosis and assessment (see web addenda)

The diagnosis and assessment of SCAD involves clinical evaluation,including identifying signi?cant dyslipidaemia,hyperglycaemia or other biochemical risk factors and speci?c cardiac investigations such as stress testing or coronary imaging.These investigations may be used to con?rm the diagnosis of ischaemia in patients with sus-pected SCAD,to identify or exclude associated conditions or pre-cipitating factors,assist in stratifying risk associated with the disease and to evaluate the ef?cacy of treatment.In practice,diagnostic and prognostic assessments are conducted simultaneously,rather than separately,and many of the investigations used for diagnosis also offer prognostic information.However,for the purpose of clarity,the processes of obtaining diagnostic and prognostic information are dealt with separately in this text.

6.1Symptoms and signs (see web addenda)

A careful history remains the cornerstone of the diagnosis of chest pain.In the majority of cases,it is possible to make a con?dent diag-nosis on the basis of the history alone,although physical examination and objective tests are often necessary to con?rm the diagnosis,

exclude alternative diagnoses,48and assess the severity of underlying disease.

The characteristics of discomfort-related to myocardial ischaemia (angina pectoris)may be divided into four categories:location,character,duration and relationship to exertion and other exacerbat-ing or relieving factors.The discomfort caused by myocardial 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 ?ngers.

The discomfort is often described as pressure,tightness or heavi-ness;sometimes strangling,constricting or burning.It may be useful to directly ask the patient for the presence of ‘discomfort’as many do not feel ‘pain’or ‘pressure’in their chest.Shortness of breath may ac-company angina,and chest discomfort may also be accompanied by less-speci?c symptoms such as fatigue or faintness,nausea,burning,restlessness or a sense of impending doom.Shortness of breath may be the sole symptom of SCAD and it may be dif?cult to differen-tiate this from shortness of breath caused by bronchopulmonary disease.

The duration of the discomfort is brief—no more than 10min in the majority of cases and more commonly even minutes or less—but chest pain lasting for seconds is unlikely to be due to angina.An important characteristic is the relationship to exercise,speci?c activ-ities or emotional stress.Symptoms 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 dis-appear within a few minutes when these causal factors abate.Exacer-bations of symptoms after a heavy meal or after waking up in the morning are classical features of angina.Angina may be reduced with further exercise (walk-through angina)or on second exertion (warm-up angina).49Buccal or sublingual nitrates rapidly relieve angina.The angina threshold—and hence symptoms—may vary con-siderably from day to day and even during the same day.

De?nitions of typical and atypical angina have been previously pub-lished and are summarized in Table 4.50Atypical angina is most fre-quently chest pain resembling that of typical angina in location and character,that is responsive to nitrates but has no precipitating factors.Often,the pain is described as starting at rest from a low level of intensity,which slowly intensi?es,remains at its maximum for up to 15min and then slowly decreases in intensity.This charac-teristic description should alert the clinician to the possibility that coronary vasospasm is present.51Another atypical presentation is pain of anginal location and quality,which is triggered by exertion ESC Guidelines

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involve only a small portion of the left or right hemithorax,and last for several hours or even days.It is usually not relieved by nitrogly-cerin(although it may be in the case of oesophageal spasm)and may be provoked by palpation.Non-cardiac causes of pain should be evaluated in such cases.48

The Canadian Cardiovascular Society classi?cation is widely used as a grading system for stable angina,53to quantify the threshold at which symptoms occur in relation to physical activities(Table5).It is,however,important to keep in mind that the grading system expli-citly recognizes that rest pain may occur in all grades as a manifest-ation of associated and superimposed coronary vasospasm.5It is also important to remember that the class assigned is indicative of the maximum limitation and that the patient may do better on other days.

Patients with chest pain are often seen in general practice.Applying a well-validated prediction rule containing the?ve determinants[viz. age/sex(male≥55years,female≥65years);known vascular disease;patient assumes pain is of cardiac origin;pain is worse during exercise and pain is not reproducible by palpation:one point for each determinant]leads to accurate ruling-out of CAD at a speci?city of81%(≤2points)and a sensitivity of87%(3–5 points).54This rule should be used in the context of other clinical in-formation,such as the presence of cough or stinging pain(making CAD more unlikely).In contrast,clinical features such as radiation of pain into the left arm,known heart failure and diabetes mellitus make CAD more likely.55

Physical examination of a patient with(suspected)angina pectoris is important to assess the presence of anaemia,hypertension,valvular heart disease,hypertrophic obstructive cardiomyopathy or arrhyth-mias.It is also recommended that practitioners obtain the body mass index(BMI)and search for evidence of non-coronary vascular disease—which may be asymptomatic[includes palpation of or meta-analyses of these studies.

6.2.1Basic testing

Before any testing is considered one must assess the general health, comorbidities and quality of life(QoL)of the patient.If assessment suggests that revascularization is unlikely to be an acceptable option,further testing may be reduced to a clinically indicated minimum and appropriate therapy should be instituted,which may

include a trial of anti-anginal medication even if a diagnosis of

SCAD has not been fully demonstrated.

Basic(?rst-line)testing in patients with suspected SCAD includes standard laboratory biochemical testing(Table6),a resting ECG

(Table8),possibly ambulatory ECG monitoring(if there is clinical sus-

picion that symptoms may be associated with a paroxysmal arrhythmia)(Table10),resting echocardiography(Table9)and,in selected patients,a chest X-ray(CXR)(Table11).Such testing can

be done on an outpatient basis.

6.2.1.1Biochemical tests(see web addenda)

Laboratory investigations are used to identify possible causes of is-chaemia,to establish cardiovascular(CV)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 thyroid disorder—thyroid hormone levels

provide information related to possible causes of ischaemia.The

full blood count,incorporating total white cell count as well as haemoglobin,may also add prognostic information.56

Fasting plasma glucose and glycated haemoglobin(HbA1c)should

be measured in every patient with suspected CAD.If both are incon-clusive,an additional oral glucose tolerance test is recom-mended.57,58Knowledge of glucose metabolism is important because of the well-recognized association between adverse cardio-vascular(CV)outcome and diabetes.Moreover,elevations of fasting

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or post-glucose challenge glycaemia have been shown to predict

adverse outcome in SCAD,independently of conventional risk factors.59Finally,glycated haemoglobin (HbA1c)predicts outcome in diabetics,as well as in non-diabetic subjects.60,61Patients with dia-

betes should be managed according to the ESC/European Associ-ation for the Study of Diabetes (EASD)Guidelines on diabetes.57

Fasting lipid pro?le,including total cholesterol (TC),high density lipoprotein (HDL)cholesterol,low density lipoprotein (LDL)choles-terol and triglycerides should also be evaluated in all patients with suspected or established ischaemic disease,including stable angina,to establish the patient’s risk pro?le and ascertain the need for

treatment.62

The lipid pro?le and glycaemic status should be re-assessed period-ically to determine ef?cacy of treatment and,in non-diabetic patients,to detect new development of diabetes (Table 7).There is no evidence to support recommendations for the frequency of re-assessment of

these risk factors.Consensus suggests annual measurement.62

Renal dysfunction may occur in association with hypertension,dia-

betes or renovascular disease and has a negative impact on prognosis in patients with stable angina pectoris.63–65Hence,baseline renal function should be evaluated with estimation of the glomerular ?ltra-tion rate (GFR)using a creatinine (or cystatin C)-based method such as the Cockcroft–Gault,66Modi?cation of Diet in Renal Disease (MDRD),67or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)formulas.68If 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 or ultrasensitive assays.If troponin is elevated,further management should follow the non-ST-elevation acute coronary syndrome (NSTE-ACS)guide-lines.1As troponins have a central role in identifying unstable patients,1,7it is recommended that troponin measurements be per-formed in every patient hospitalised for symptomatic SCAD.Very low levels of troponin can be detected in many patients with SCAD when high-sensitive assays are employed.These levels are usually below the levels de?ned as being elevated.Although there is some prognostic value associated with the amount of troponin found in stable patients,8,9troponin does not have enough independ-ent prognostic value to recommend systematic measurement in out-of-hospital patients with SCAD.

Elevated levels of high-sensitivity C-reactive protein (hs-CRP)have also been reported to be associated with an increased event risk in patients with SCAD.However,a recent analysis of 83studies found multiple types of reporting and publication bias,making the magnitude of any independent association between hs-CRP and prognosis among patients with SCAD suf?ciently uncer-tain that no recommendation can be made to routinely measure this parameter.69

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All patients with suspected CAD should have a resting12-lead ECG

recorded.A normal resting ECG is not uncommon,even in patients with severe angina,and does not exclude the diagnosis of ischaemia. However,the resting ECG may show signs of CAD,such as previous MI or an abnormal repolarization pattern.An ECG will establish a baseline for comparison in future situations.

The ECG may assist in clarifying the differential diagnosis if taken in the presence of pain,allowing detection of dynamic ST-segment changes in the presence of ischaemia.An ECG during chest pain and immediately afterwards is always useful and can be diagnostic in patients with vasospasm,since ST segment shifts tend to be at least partially reversible once spasm is relieved.The ECG may also show other abnormalities such as left ventricular hypertrophy (LVH),left or right bundle branch block(LBBB or RBBB),pre-excitation,arrhythmias,or conduction defects.Such information may be helpful in de?ning the mechanisms responsible for chest pain(atrial?brillation may be associated with chest discomfort without epicardial coronary disease)78in selecting appropriate further investigations,or in tailoring individual patient treatment. The resting ECG also has a role in risk strati?cation,as outlined later.

6.2.1.3Echocardiography at rest(see web addenda)

Resting two-dimensional and Doppler transthoracic echocardiography provide information on cardiac structure and function.Although left ventricular(LV)function is often normal in these patients,regional wall motion abnormalities may be detected,which increase the likeli-hood of CAD.Furthermore other disorders,such as valvular heart disease(aortic stenosis)or hypertrophic cardiomyopathy,can be ruled out as an alternative cause of symptoms.Finally,global ventricular function,an importantprognosticparameterin patientswith SCAD,29,79can be measured.Echocardiography is particularly useful in patients with murmurs80,previous MI or symptoms/signs of heart failure.

Once resting echocardiography has been performed,ultrasound

of the carotid arteries using an appropriate probe may be added by clinicians trained in the examination.81,82The detection of increased

intima-media thickness and/or plaques establishes the presence of atherosclerotic disease,with consequent implications for preventive therapy,37and increases the pre-test probability of CAD in subse-

quent diagnostic tests.83

Tissue Doppler imaging and strain rate measurements may also be

helpful in detecting heart failure with preserved EF as an explanation

for physical activity-associated symptoms.84Impaired diastolic?lling

is the?rst sign of active ischaemia and may point to the presence of microvascular dysfunction in patients who complain about shortness

of breath,as a possible angina equivalent.85,86

Although the diagnostic yield of echocardiography in patients with

angina is mainly concentrated in speci?c subgroups,estimation of ven-

tricular function is important in all patients for risk strati?cation(see

section6.4).Hence,echocardiography(or alternative methods of as-sessment of ventricular function if echocardiography is of insuf?cient quality)should be performed in all patients with a?rst presentation

with symptoms of SCAD.

There is no indication for repeated use of resting echocardiog-

raphy on a regular basis in patients with uncomplicated SCAD in

the absence of a change in clinical status.

6.2.1.4Cardiac magnetic resonance at rest

Cardiac magnetic resonance(CMR)may also be used to de?ne struc-

tural cardiac abnormalities and evaluate ventricular function.87Use of

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by the stress test.88Neither is there good evidence to support routine deployment of ambulatory ECG monitoring as a tool for re?ned prognostication.

Ambulatory monitoring,however,has a role in patients in whom arrhythmias or vasospastic angina are suspected(equipment for ST-segment evaluation required).

6.2.1.6Chest X-ray

A CXR is frequently used in the assessment of patients with chest pain:however,in SCAD,the CXR does not provide speci?c of diagnostic tests to generate individualized post-test disease prob-abilities for a given patient.The PTP is in?uenced by the prevalence of

the disease in the population studied,as well as clinical features(in-cluding the presence of CV risk factors)of an individual.90Major determinants of PTP are age,gender and the nature of symptoms.90 Sensitivity and speci?city are often used to describe the accuracy of

a given diagnostic method,but they incompletely describe how a test performs in the clinical setting.First,some diagnostic methods may perform better in some patients than in others—such as coronary computed tomography angiography(CTA),which is sensitive to

heart rate,body weight and the presence of calci?cation.Second,al-though sensitivity and speci?city are mathematically independent

from the PTP,in clinical practice many tests perform better in

low-risk populations;in the example used above,coronary CTA

will have higher accuracy values when low-likelihood popula-tions—which are younger and have less coronary calcium—are sub-

jected to the examination.

Because of the interdependence of PTP(the clinical likelihood that

a given patient will have CAD)and the performance of the available diagnostic methods(the likelihood that this patient has disease if the

test is positive,or does not have disease if the test is negative),recom-mendations for diagnostic testing need to take into account the PTP. Testing may do harm if the number of false test results is higher than

the number of correct test results.Non-invasive,imaging-based diag-

nostic methods for CAD have typical sensitivities and speci?cities of approximately85%(Table12).Hence,15%of all diagnostic results

will be false and,as a consequence,performing no test at all will provide fewer incorrect diagnoses in patients with a PTP below

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ing all patients to be diseased).In these situations,testing should only be done for compelling reasons.This is the reason why this Task Force recommends no testing in patients with(i)a low PTP,15% and(ii)a high PTP.85%.In such patients,it is safe to assume that they have(i)no obstructive CAD or(ii)obstructive CAD.

The low sensitivity of the exercise ECG—only50%(despite an ex-cellent speci?city of90%,values obtained from studies avoiding veri-?cation bias)91—isthe reason why the number of false test results will become higher than the number of correct test results in populations with a PTP.65%.92Therefore,this Task Force recommends not employing the exercise stress test in such higher-risk populations for diagnostic purposes.However,the test may nevertheless provide valuable prognostic information in such populations.93

In this new version of the Guidelines,more weight is given to testing based systematically on consideration of pre-test probabil-ities.107This Task Force selected the most recent estimates of CAD prevalences as the basis of these Guidelines’clinical algo-rithm,108as discussed in the web addenda and shown in Table13. The web addenda also contains more information about changes from the previous Stable Angina guidelines of the ESC and the reasons why ECG exercise testing was kept in the algorithm.

If the pain is clearly non-anginal other diagnostic testing may be indi-cated to identify gastrointestinal,pulmonary or musculoskeletal causes of chest pain(Figure1).Nevertheless,these patients should also receive risk factor modi?cation based on commonly applied risk charts such as SCORE(929cf97c5022aaea998f0fc9/Pages/welcome. aspx)or the Framingham risk score(929cf97c5022aaea998f0fc9/atpiii/ calculator.asp).Patientswithsuspected SCAD,in whom comorbidities make revascularization inadvisable,should be treated medically but pharmacologic stress imaging may be an option if it appears necessary to verify the diagnosis.Patients with a reduced left ventricular ejection

fraction(LVEF)of,50%and typical angina are at high risk for cardio-vascular events(see later in the text)and they should be offered ICA

without previous testing(see Figure1).

Patients in whom anginal pain may be possible but who have a very

low probability of signi?cant CAD,15%should have other cardiac

causes of chest pain excluded and their CV risk factors adjusted,

based on risk score assessment.37No speci?c non-invasive stress

testing should be performed.92In patients with repeated,unpro-

voked attacks of chest pain only at rest,vasospastic angina should

be considered and diagnosed,and treated appropriately(see below).Patients with an intermediate PTP of15–85%should undergo further non-invasive testing.In patients with a clinical PTP

.85%,the diagnosis of CAD should be made clinically and further

testing will not improve accuracy.Further testing may,however,be indicated for strati?cation of risk of events,especially if no satisfactory

control of symptoms is possible with initial medical therapy(Figure1).

In patients with severe angina at a low level of exercise and those with

a clinical constellation indicating a high event risk,109proceeding dir-

ectly to ICA is a reasonable option.Under such circumstances,the indication for revascularization should depend on the result of intra-procedural fractional?ow reserve(FFR)testing when indicated.110

The very high negative predictive value of a coronary CTA showing

no stenoses can reassure patients and referring physicians that insti-

tuting medical therapy and not proceeding to further testing or inva-

sive therapies is a good strategy.This makesthe test potentially useful, especially for patients at low intermediate PTPs(Figure2).One

should remember that there may be overdiagnosis of stenoses in patients with Agatston scores.400,104,105and it seems prudent to

call a coronary CTA‘unclear’if severe focal or diffuse calci?cations

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prevent an unambiguous identi?cation of the vessel lumen (see Figure 2).To obtain optimal results,published professional standards need to be meticulously adhered to.111With these caveats in mind,coronary CTA may be considered to be an alternative to ischaemia testing,especially in patients with chest pain symptoms at intermedi-ate PTPs lower than 50%.1126.2.4Stress testing for diagnosing ischaemia 6.2.4.1Electrocardiogram exercise testing Because of its simplicity and widespread availability,treadmill or bicycle exercise testing,using 12-lead ECG monitoring,remains a useful option (Table 14)in patients with suspected SCAD and a PTP (15–65%)at which the test performs well (see above).A detailed description of the exercise procedure,its interpretation,the in?uence of drugs and other factors on test performance,and test performance in special groups can be found in the previous version of these Guidelines on the ESC website.3

The main diagnostic ECG abnormality during ECG exercise testing

consists of a horizontal or down-sloping ST-segment depression

≥0.1mV,persisting for at least 0.06–0.08s after the J-point,in one or more ECG leads.It is worth noting that,in about 15%of patients,diagnostic ST-segment changes appear only during the recovery Consider comorbidities and QoL Cause of chest pain other than CAD?LVEF <50%?Typical angina?

Treat as appropriate

Yes Yes No Comorbidities or QoL make

revascularization unlikely ECG Bio-Chemistry Resting

echocardiography a CXR in

selected

patients

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phase.The test also provides additional information,such as heart rate response,blood pressure response,symptoms,and workload achieved,which has both diagnostic and prognostic relevance.To obtain maximal diagnostic information from exercise ECG testing,the latter should be symptom/sign-limited and performed without the in?uence of anti-ischaemic drugs.There are numerous reviews and meta-analyses of the performance of exercise ECG for the diagnosis of coronary disease,showing variable diagnostic yield according to the threshold selected for the 929cf97c5022aaea998f0fc9ing exercise ST-depression ≥0.1mV or 1mm to de?ne a positive test,the reported sensitivities and speci?cities for the detection of signi?cant CAD (usually diameter stenoses ≥50%)range between 23–100%(mean 68%)and 17–100%(mean 77%),respectively 91.Restricting the analysis to those studies designed to avoid work-up bias,sensitiv-ities between 45–50%and speci?cities of 85–90%were reported (Table 12).94,95Adding cardiopulmonary exercise testing may improve sensitivity signi?cantly,113but this combination of tests is not widely used.It is important to remember that these numbers are valid only in patients without signi?cant ECG abnormalities at baseline.Exercise ECG testing is not of diagnostic value in the presence of LBBB,paced rhythm and Wolff-Parkinson-White syndrome,in which cases the ECG changes are not interpretable.Additionally,false-positive results are more frequent in patients with abnormal resting ECG in the presence of LVH,electrolyte imbalance,intraventricular conduction abnormalities,atrial ?brillation,78,114and use of digitalis.Exercise ECG testing is also less sensitive and speci?c in women.95However,a recent randomized trial,comparing an initial diagnostic strategy of exercise nuclear myocardial perfusion imaging (MPI)with standard exercise treadmill testing,in symptomatic women with suspected CAD and preserved functional capacity who were able to exercise,did not show an incremental bene?t of the more ex-pensive MPI strategy on clinical outcomes.115

In some patients,the exercise ECG may be inconclusive;for example,when 85%of maximum heart rate is not achieved in the absence of symptoms or signs of ischaemia,when exercise is

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limited by orthopaedic or other non-cardiac problems,or when ECG changes are equivocal.In these patients,an alternative non-invasive imaging test with pharmacologic stress should be selected (Figure 2).In patients who are appropriately selected (Figure 2),cor-onary CTA is another option.Furthermore,a ‘normal’ECG stress test in patients taking anti-ischaemic drugs does not rule out signi?-cant coronary disease.

Exercise stress testing can also be useful to evaluate the ef?cacy of medical treatment or after revascularization,or to assist prescription of exercise after control of symptoms.For these indications,exercise stress testing should be performed on treatment to evaluate control of ischaemia or effort performance.The effect of routine periodic ex-ercise testing on patient outcomes has not been formally evaluated.6.2.4.2Stress imaging (see web addenda)

6.2.4.2.1Stress echocardiography .Stress echocardiography is per-formed with exercise (treadmill or bicycle ergometer)or with pharmacological agents.121Exercise provides a more physiological environment than pharmacological tests and provides additional physiological data,such as exercise time and workload,as well as in-formation about changes in heart rate,blood pressure and ECG.Thus,exercise is the test of choice when feasible (Table 15).

On the other hand,a pharmacological test is preferred when there is already a signi?cant resting wall motion abnormality (dobutamine for viability assessment)and/or if the patient is unable to exercise ad-equately.Until recently,stress echocardiography relied on inducible wall thickening abnormalities as a marker of ischaemia (supply–demand mismatch).As most data on diagnostic accuracy were obtained using this standard,there is a caveat,in that the values for sensitivity and speci?city assumed in these guidelines (Table 12)rely heavily on old studies,carried out at a time when contrast media were not broadly utilized in clinical practice.

The pharmacological agent of choice to produce supply-demand mismatch is dobutamine.Myocardial contrast echocardiography,which utilizes microbubbles,allows assessment of myocardial perfu-sion,which provides information beyond wall thickening assessment during both vasodilatorand inotropic stress echocardiography.122,123This approach,however,is not widely employed clinically.

Contrast agents must be used in all patients undergoing all forms of stress echocardiography when two or more continuous segments (17segment LV model)are not well visualised at rest.122The use of contrast during stress echocardiography not only enhances image quality,but improves reader con?dence and enhances

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accuracy for the detection of CAD.122,124Tissue Doppler imaging and strain rate imaging may also improve the diagnostic performance of stress echocardiography by improving the capability of echocardi-ography to detect ischaemia beyond wall motion assessment.1256.2.4.2.2Myocardial perfusion scintigraphy (single photon emission com-puted tomography and positron emission tomography).Technetium-99m (99m Tc)radiopharmaceuticals are the most commonly used tracers,employed with single photon emission computed tomography (SPECT)in association with a symptom-limited exercise test on either a bicycle ergometer or a treadmill (Table 15).Thallium 201(201Tl)is associated with a higher radiation and is less commonly used today.New SPECT cameras reduce radiation and/or acquisition time signi?cantly.126

Regardless of the radiopharmaceutical or camera used,SPECT perfusion scintigraphy is performed to produce images of regional tracer uptake,which re?ect relative regional myocardial blood ?ow.With this technique,myocardial hypoperfusion is characterized by reduced tracer uptake during stress,in comparison with the uptake at rest.Increased uptake of the myocardial perfusion agent in the lung ?eld identi?es stress-induced ventricular dysfunction in patients with severe and extensive CAD.127As with all stress imaging techniques,SPECT perfusion also provides a more sensitive prediction of the presence of CAD than the exercise ECG (Table 12).Transient ischaemic dilatation and reduced post-stress ejection frac-tion (EF)are important non-perfusion predictors of severe CAD.Pharmacological stress testing with perfusion scintigraphy is indi-cated in patients who are unable to exercise adequately or may be used as an alternative to exercise stress.Adenosine may precipitate bronchospasm in asthmatic individuals by activating A 1,A 2B and A 3receptors in addition to activation of the A 2A adenosine receptor,which produces hyperaemia.This limitation exists irrespective of the imaging technique used but,in such cases,dobutamine or regade-noson,128a selective A 2A receptor agonist,may be used as an alterna-tive stressor.

MPI using positron emission tomography (PET)is superior to SPECT imaging for the detection of SCAD in terms of image quality,interpretative certainty and diagnostic accuracy.129However,SPECT scanners and imaging radiotracers are more widely available and less expensive than PET scanners and positron-emitting radiotra-cers (e.g.82Rb,13N-ammonia).130Hence,as compared with the other stress imaging techniques,PET is less commonly used for diagnosing SCAD.PET has the unique ability to quantify blood ?ow in mL/min/g,which allows detecting microvascular disease.131

6.2.4.2.3Stress cardiac magnetic resonance .Cardiac magnetic reson-ance (CMR)stress testing,in conjunction with a dobutamine infusion,can be used to detect wall motion abnormalities induced by ischae-mia.132The technique has been shown to have a comparable safety pro?le to dobutamine stress echocardiography (DSE).133,134Dobu-tamine stress CMR may be useful in patients with sub-optimal acous-tic windows,132,135especially those in whom pharmacologic perfusion imaging using adenosine is contra-indicated (Table 15).Perfusion CMR is more widely used than dobutamine stress CMR.Recent studies have con?rmed the good diagnostic accuracy of CMR perfusion imaging at 1.5Tesla (T),as compared with nuclear perfu-sion imaging.102,136

Details regarding stress and imaging protocols were recently reviewed.137Analysis is either visual,to identify low signal areas of

reduced perfusion,or with computer assistance to determine the up-slope of myocardial signal increase during the ?rst pass.Quantita-tive CMR perfusion measurements demonstrate good correlations with FFR measurements.138Although not widely available,the use of high-strength magnets at 3.0T provides higher diagnostic accuracy,as compared with 1.5T machines.139,140

6.2.4.2.4Hybrid techniques .Hybrid SPECT/CT,PET/CT and PET/CMR imaging are now available at a few selected centres.Hybrid imaging is a novel technique combining functional and anatomical aspects,which holds much promise for future clinical application.The limited evidence available today indicates a higher diagnostic ac-curacy,as compared with single techniques.141Initial reports also point to the prognostic value of hybrid imaging.142

6.2.5Non-invasive techniques to assess coronary anatomy 6.2.5.1Computed tomography

Spatial resolution and temporal resolution,as well as volume cover-age of modern multidetector row CT systems,are suf?cient to allow robust imaging of the coronary arteries in many patients.150Radiation dose is a matter of concern and special measures need to be under-taken to avoid unnecessarily high radiation doses when CT is used for coronary artery imaging.151CT imaging of the coronary arteries can be performed without contrast injection (coronary calcium scoring)or after intravenous injection of iodinated contrast (coronary CTA).6.2.5.1.1Calcium scoring .Multidetector row CT permits the detec-tion of coronary calci?cation in non-contrast enhanced data sets.By consensus,pixels above a threshold of 130Houns?eld units (HU)are de?ned as representing coronary calcium.Calci?ed lesions are usually quanti?ed using the ‘Agatston score’.152

With the exception of patients with renal failure—who may have medial calci?cation—coronary calcium is exclusively a conse-quence of coronary atherosclerosis.The amount of calcium corre-lates roughly to the total amount of atherosclerosis present in the coronary arteries,153but correlation with the degree of luminal narrowing is poor.Even with severe calci?cation,luminal stenosis is not necessarily present and a ‘zero’calcium score cannot be used to rule out coronary artery stenoses in symptomatic individuals (Table 16),especially when young and with acute symptoms.154

6.2.5.1.2Coronary computed tomography angiography .After intraven-ous injection of contrast agent,CT can visualize the coronary artery lumen.Adequate technology (at least 64-slice CT)and patient selection,as well as careful patient preparation,are mandated.According to expert consensus,only patients with adequate breath holding capabilities,without severe obesity,with a favourable calcium score (e.g.Agatston score ,400)and distribution,in sinus rhythm and with a heart rate of 65beats per minute (b.p.m.)or less (preferably 60b.p.m.or less),should be considered for coronary CTA.111If necessary,the use of short-acting b -blockers or other heart rate-lowering medication is recommended.

Since the speci?city of coronary CTA decreases with increasing amounts of coronary calcium,103,155,156and the prevalence of coron-ary artery stenosis was found to be high in symptomatic individuals with an Agatston score .400,157it is reasonable not to proceed with coronary CTA if the calcium score exceeds 400.158However,on a patient level,per-segment calci?cation has a stronger in?uence on diagnostic accuracy than calcium,159and the in?uence of calcium

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onthe accuracyof coronary CTA is less pronounced in low heart rates and for modern CT systems.160,161In the event that a calcium score is not obtained and calci?cations are only seen on the completed coron-ary CTA scan,it may be prudent to refrain from stenosis quanti?cation in areas of extensive calci?cations and call the test ‘unclear’(see Figure 2).In patients with suspected CAD,multicentre studies using 64-slice CT have demonstrated sensitivities of 95–99%and speci?cities of 64–83%(Table 12)as well as negative predictive values of 97–99%for the identi?cation of individuals with at least one coronary artery stenosis by ICA.103,105Meta-analyses of smaller trials

con?rm a high sensitivity (98–99%)and negative predictive value (99–100%),paired with lower speci?city (82–89%)and positive pre-dictive value (91–93%).162In a multicentre study,which included patients with previously known CAD,previous PCI and MI,diagnostic accuracy was lower (sensitivity 85%and speci?city 90%).104Severe coronary calcium negatively impacts the accuracy of coronary CTA.155,159Also,coronary CTA remains less reliable in patients with coronary stents,due to artefacts caused by metal and the limited spatial resolution of CT.The assessment of coronary artery bypass grafts (CABG)is highly accurate while the evaluation of native coronary vessels in post-bypass patients is dif?cult and prone to false positive ?ndings.163,164Whilst prospective trials—which have randomized patients to the

use or non-use of coronary CTA looking at hard clinical endpoints in stable chest pain patients—are currently not available (just as for the other imaging techniques),registry data con?rm an excellent progno-sis if coronary CTA demonstrates the absence of coronary artery stenoses.165–167Indications for coronary CTA are summarized in Figure 2.The diagnostic performance of coronary CTA is best for indivi-duals at the lower range of intermediate PTP for the disease.162,168Thus,coronary CTA may be useful in ruling out coronary stenoses in such patients if—based on patient characteristics as described above—good image quality and a reasonably low radiation exposure can be expected and if adequate technology and expertise are avail-able.Under the same prerequisites,coronary CTA should also be considered in patients with a stress test result that contradicts clinical judgement (especially a positive stress test result when clinical judg-ment speaks against the presence of severe stenoses)if ICA would otherwise be chosen to rule out CAD (Table 16).Given the false-positive rate of stress tests in some populations,such as patients with LVH,coronary CTA may be warranted as a ?rst-line test in selected individuals.However,coronary CTA cannot rule out functional CAD in these patients.No data are available to support ‘screening’coronary CTA in asymptomatic individuals and CTA should not be used for this purpose.2New developments in coronary CTA,such as CT-FFR need further validation.1696.2.5.2Magnetic resonance coronary angiography Coronary MR angiography allows for non-invasive visualization of the coronary arteries without exposing the patient to ionizing radiation.A recent small,multicentre study showed sensitivity,speci?city and positive and negative predictive values of 88,72,71and 88%,respect-ively,in a patient-based analysis.170However,long imaging times,lower spatial resolution and operator dependency remain major lim-itations.171Advantages of the technique include evaluation of overall cardiac anatomy and function in the same examination.However,at present,MR coronary arteriography must still be regarded primarily as a research tool and is not recommended for routine clinical prac-tice in the diagnostic evaluation of SCAD.

6.3Invasive coronary angiography (see web addenda)

Non-invasive testing can establish the likelihood of the presence of obstructive coronary disease with an acceptable degree of certainty.Thus,ICA will only rarely be necessary in stable patients with sus-pected CAD,for the sole purpose of establishing or excluding the diagnosis.Such situations may arise in patients who cannot undergo stress imaging techniques,172in patients with reduced LVEF ,50%and typical angina (see Figure 1)or in those patients with special professions,such as pilots,due to regulatory issues.ICA may,however,be indicated following non-invasive risk strati?ca-tion for determination of options for revascularization.In patients who have a high PTP and severe symptoms,or a clinical constellation suggesting high event risk,early ICA without previous non-invasive

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risk strati?cation may be a good strategy to identify lesions potentially amenable to revascularization (see Figure 1).FFR testing is advised if appropriate.172Methods used to perform ICA have improved substantially,result-ing in the reduction of complication rates with rapid ambulation.This is especially true for ICA performed via the radial artery.173The com-posite rate of major complications associated with routine femoral diagnostic catheterization—mainly bleeding requiring blood transfu-sions—is still between 0.5–2%.174The composite rate of death,MI,or stroke is of the order of 0.1–0.2%.175ICA should not be performed in patients with angina who refuse invasive procedures,prefer to avoid revascularization,who are not candidates for PCI or 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 brie?y mentioned in the web addenda of this document.6.4Strati?cation for risk of events The long-term prognosis of SCAD depends upon a number of factors,such as clinical and demographic variables,LV function,the result of stress testing and coronary anatomy as determined by angio-

graphic techniques.When discussing risk strati?cation in patients with SCAD,event risk refers primarily to the risk of CV death and MI,although in some studies even wider combinations of CV endpoints are employed.As all-cause death is more precisely de?ned than other

weaker endpoints—including MI—these guidelines stratify event risk according to this hard endpoint.The process of risk strati?cation serves to identify patients at high event risk who will bene?t from revascularization beyond the amelioration of symptoms.The de?nition of the high event risk group of patients who will bene?t from revascularization has changed from the previous version of these Guidelines.Previously,identi?cation of high event risk was solely based on the Duke treadmill score and a .2%annual risk of cardiac death was felt to be the threshold beyond which coronary angiography was recommended to identify the need for revascularization.3This value was based on the CV mortality in the placebo arms of studies in ‘high-risk’populations,such as in the diabetic Microalbuminuria,cardiovascular,and renal sub-study of the Heart Outcomes Prevention Evaluation study (MICRO-HOPE)176and the Impact Of Nicorandil in Angina (IONA)177studies,where the annualized CV mortality rates were .2%.

In these Guidelines,patients with an annual mortality .3%are de?ned as high event risk patients.As shown in the web addenda,both ischaemia-and anatomy-oriented indices come to similar con-clusions in identifying which patients are at such high event risk with medical treatment alone that revascularization procedures become bene?cial in terms of prognosis.Therefore,in these Guidelines,it is the goal of a event risk-driven diagnostic strategy to identify patients with an annual mortality .3%per year.

For the purpose of these Guidelines,low event risk patients are

those with an annual mortality ,1%per year,similar to the de?nition

chosen in the previous edition.3The intermediate event risk group

has an annual mortality of ≥1%but ≤3%per year (Table 17).The risk assessment sequence can be described as:

(1)Risk strati?cation by clinical evaluation

(2)Risk strati?cation by ventricular function

(3)Risk strati?cation by response to stress testing

(4)Risk strati?cation by coronary anatomy.

Event risk strati?cation generally follows a pyramidal structure,with all patients having event risk strati?cation by clinical evaluation as the most basic requirement,proceeding to assessment of ventricular function by resting echocardiography and,in the majority,to non-invasive assessment of ischaemia/coronary anatomy (which is usually obtained in the process of making a diagnosis of SCAD,as dis-cussed above).ICA for risk strati?cation will only be required in a selected subgroup of patients.

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6.4.1Event risk strati?cation using clinical evaluation Clinical history and physical examination can provide important prognostic information.The ECG can be conveniently incorporated into the event risk strati?cation at this level and the results of the la-boratory tests discussed in the previous section may modify event risk estimation further.Diabetes,hypertension,current smoking and elevated TC (untreated or elevated despite treatment)have been shown to be predictive of adverse outcome in patients with SCAD or other populations with established coronary disease.178In-creasing age is an important factor to consider,as are the presence of chronic kidney-or peripheral vascular disease,65,179prior MI,180symptoms and signs of heart failure,180,181and the pattern of occur-rence (recent onset or progressive)and severity of angina,particular-ly if unresponsive to therapy.45,182However,this information is too complex to be placed into a clinically useful event risk score for patients with SCAD and the recommendation is therefore to use the data—especially the severity of angina—to modulate decisions made on the basis of PTP and non-invasive ischaemia/anatomy evalu-ation of the prognosis (Figure 3). 6.4.2Event risk strati?cation using ventricular function The strongest predictor of long-term survival is LV function.In patients with SCAD as LVEF declines,mortality increases.In the Cor-onary Artery Surgery Study (CASS)registry,the 12-year survival rates of patients with EF ≥50%,35–49%and ,35%were 73,54and 21%,respectively (P ,0.0001).183Hence,a patient with an LVEF ,50%is already at high risk for CV death (annual mortality .3%),even without accounting for additional event risk factors,such as the extent of ischaemia.As a reduced LVEF ,50%confers such an important increase in event risk,it may be important not to miss obstructed vessels causing ischaemia in such patients.184,185Hence,stress imaging should be employed instead of the exercise ECG (Figure 2).

Although the likelihood of preserved ventricular systolic function is high in patients with a normal ECG,a normal CXR and no history of prior MI,186asymptomatic ventricular dysfunction is not uncommon.187Therefore,as already discussed above,a resting echo-cardiogram is recommended in all patients with suspected SCAD (Table 18).

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