•
UFPA
Maju Rocha 04/10/2024
See Also
Pub - Clinical Outline of Oral Pathology Diagnosis and T PDF - PDFCOFFEE.COMUS Patent Application for SUBSTITUTED NITROGEN CONTAINING COMPOUNDS Patent Application (Application #20240327390 issued October 3, 2024)US Patent Application for BENZAMIDES AND NICOTINAMIDES AS SYK MODULATORS Patent Application (Application #20150038492 issued February 5, 2015)Grand Traverse Herald, May 29, 1913 · TADL Local History CollectionPrévia do material em texto
<p>2019 ESC Guidelines for the diagnosis and</p><p>management of chronic coronary syndromes</p><p>The Task Force for the diagnosis and management of chronic</p><p>coronary syndromes of the European Society of Cardiology (ESC)</p><p>Authors/Task Force Members: Juhani Knuuti* (Finland) (Chairperson),</p><p>William Wijns* (Ireland) (Chairperson), Antti Saraste (Finland), Davide Capodanno</p><p>(Italy), Emanuele Barbato (Italy), Christian Funck-Brentano (France),</p><p>Eva Prescott (Denmark), Robert F. Storey (United Kingdom), Christi Deaton</p><p>(United Kingdom), Thomas Cuisset (France), Stefan Agewall (Norway),</p><p>Kenneth Dickstein (Norway), Thor Edvardsen (Norway), Javier Escaned (Spain),</p><p>Bernard J. Gersh (United States of America), Pavel Svitil (Czech Republic),</p><p>Martine Gilard (France), David Hasdai (Israel), Robert Hatala (Slovak Republic),</p><p>Felix Mahfoud (Germany), Josep Masip (Spain), Claudio Muneretto (Italy),</p><p>Marco Valgimigli (Switzerland), Stephan Achenbach (Germany), and Jeroen J. Bax</p><p>(Netherlands)</p><p>Document Reviewers: Franz-Josef Neumann (Germany) (CPG Review Coordinator), Udo Sechtem</p><p>(Germany) (CPG Review Coordinator), Adrian Paul Banning (United Kingdom), Nikolaos Bonaros</p><p>(Austria), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Alaide Chieffo (Italy), Filippo Crea (Italy),</p><p>Martin Czerny (Germany), Victoria Delgado (Netherlands), Paul Dendale (Belgium),</p><p>* Corresponding authors: Juhani Knuuti, Department of Clinical Physiology, Nuclear Medicine and PET and Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-</p><p>20520 Turku, Finland. Tel: þ358 500 592 998, Email: juhani.knuuti@tyks.fi. William Wijns, The Lambe Institute for Translational Medicine and Curam, National University of</p><p>Ireland, Galway, University Road, Galway, H91 TK33, Ireland. Tel: þ353 91 524411, Email: william.wyns@nuigalway.ie.</p><p>Author/Task Force Member Affiliations: listed in the Appendix.</p><p>ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.</p><p>ESC entities having participated in the development of this document:</p><p>Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular</p><p>Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm</p><p>Association (EHRA), Heart Failure Association (HFA).</p><p>Councils: Council for Cardiology Practice.</p><p>Working Groups: Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation,</p><p>Thrombosis.</p><p>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-</p><p>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</p><p>publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).</p><p>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</p><p>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-</p><p>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-</p><p>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, diagnostic, or</p><p>therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and</p><p>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</p><p>the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent</p><p>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</p><p>health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.</p><p>VC The European Society of Cardiology 2019. All rights reserved. For permissions please email: journals.permissions@oup.com.</p><p>European Heart Journal (2020) 41, 407�477</p><p>ESC GUIDELINES</p><p>doi:10.1093/eurheartj/ehz425</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>mailto:</p><p>mailto:</p><p>mailto:</p><p>mailto:</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>Frank Arnold Flachskampf (Sweden), Helmut Gohlke (Germany), Erik Lerkevang Grove (Denmark),</p><p>Stefan James (Sweden), Demosthenes Katritsis (Greece), Ulf Landmesser (Germany), Maddalena Lettino</p><p>(Italy), Christian M. Matter (Switzerland), Hendrik Nathoe (Netherlands), Alexander Niessner (Austria),</p><p>Carlo Patrono (Italy), Anna Sonia Petronio (Italy), Steffen E. Pettersen (United Kingdom), Raffaele Piccolo</p><p>(Italy), Massimo Francesco Piepoli (Italy), Bogdan A. Popescu (Romania), Lorenz R€aber (Switzerland),</p><p>Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Franz X. Roithinger (Austria), Evgeny Shlyakhto</p><p>(Russian Federation), Dirk Sibbing (Germany), Sigmund Silber (Germany), Iain A. Simpson</p><p>(United Kingdom), Miguel Sousa-Uva (Portugal), Panos Vardas (Greece), Adam Witkowski (Poland),</p><p>Jose Luis Zamorano (Spain)</p><p>The disclosure forms of all experts involved in the development of these Guidelines are available on the</p><p>ESC website www.escardio.org/guidelines</p><p>For the Supplementary Data which include background information and detailed discussion of the data</p><p>that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/</p><p>10.1093/eurheartj/ehz425#supplementary-data</p><p>Online publish-ahead-of-print 31 August 2019</p><p>...................................................................................................................................................................................................</p><p>Keywords Guidelines • chronic coronary syndromes • angina pectoris • myocardial ischaemia • coronary artery</p><p>disease • diagnostic testing • imaging • risk assessment • lifestyle modifications • anti-ischaemic drugs •</p><p>antithrombotic therapy • lipid-lowering drugs • myocardial revascularization • microvascular angina •</p><p>vasospastic angina • screening</p><p>Table of contents</p><p>1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411</p><p>2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413</p><p>2.1 What is new in the 2019 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . 414</p><p>3. Patients with angina and/or dyspnoea, and suspected</p><p>coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416</p><p>3.1 Basic assessment, diagnosis, and risk assessment . . . . . . . . . . . . . 416</p><p>3.1.1 Step 1: symptoms and signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417</p><p>3.1.1.1 Stable vs. unstable angina . . . . . . . . . . . . . . . . . . . . . . . . . . . 418</p><p>3.1.1.2 Distinction between symptoms caused by</p><p>epicardial vs. microvascular/vasospastic disease . . . . .</p><p>Classa Levelb</p><p>If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or</p><p>ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.28,29 I A</p><p>The following blood tests are recommended in all patients:</p><p>• Full blood count (including haemoglobin);30 I B</p><p>• Creatinine measurement and estimation of renal function;31,32 I A</p><p>• A lipid profile (including LDL-C).33,34 I A</p><p>It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-</p><p>mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c</p><p>and fasting plasma glucose results are inconclusive.16,35</p><p>I B</p><p>Assessment of thyroid function is recommended in case of clinical suspicion of thyroid disorders. I C</p><p>ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein</p><p>cholesterol.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>ESC Guidelines 419</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>http://www.heartscore.org</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>3.1.3.2 Resting electrocardiogram and ambulatory monitoring</p><p>The paradigm of diagnosing myocardial ischaemia has, for almost a</p><p>century, been based on the detection of repolarization abnormalities,</p><p>mainly in the form of ST-segment depressions. Thus, the resting 12</p><p>lead ECG remains an indispensable component of the initial evalua-</p><p>tion of a patient with chest pain without an obviously non-cardiac</p><p>cause. Two scenarios of clinical evaluation are encountered: (i) a</p><p>patient without symptoms of chest pain or discomfort, and (ii) a</p><p>patient with ongoing anginal symptoms.</p><p>The former situation is far more prevalent and a normal resting</p><p>ECG is frequently recorded. However, even in the absence of repola-</p><p>rization abnormalities, an ECG can demonstrate indirect signs of</p><p>CAD, such as signs of previous MI (pathological Q waves) or conduc-</p><p>tion abnormalities [mainly left bundle branch block (LBBB) and</p><p>impairment of atrioventricular conduction]. Atrial fibrillation (AF) is a</p><p>frequent finding in patients with chest pain (usually atypical). ST-</p><p>segment depression during supraventricular tachyarrhythmias is not</p><p>predictive of obstructive CAD.36�39</p><p>The ECG can be crucial for diagnosing myocardial ischaemia if</p><p>dynamic ST-segment changes are recorded during ongoing angina.</p><p>The diagnosis of Prinzmetal and vasospastic angina is based on the</p><p>detection of typical transient ST-segment elevation or depression</p><p>during an angina attack (usually at rest).</p><p>Long-term ambulatory ECG monitoring and recording should not</p><p>be used to replace exercise testing; however, 12 lead ECG monitor-</p><p>ing can be considered in selected patients to detect anginal episodes</p><p>unrelated to physical exercise. Ambulatory ECG monitoring may</p><p>reveal evidence of silent myocardial ischaemia in patients with</p><p>CCS, but rarely adds relevant diagnostic or prognostic information</p><p>that cannot be derived from stress testing.40 ECG changes suggesting</p><p>ischaemia on ambulatory ECG monitoring are very frequent in</p><p>women, but do not correlate with findings during stress testing.41</p><p>Most importantly, therapeutic strategies targeting silent ischaemia</p><p>detected by ambulatory monitoring have not demonstrated clear</p><p>survival benefits.42,43</p><p>3.1.3.3 Echocardiography and magnetic resonance imaging at rest</p><p>An echocardiographic study will provide important information about</p><p>cardiac function and anatomy. LV ejection fraction (LVEF) is often nor-</p><p>mal in patients with CCS.44 A decreased LV function and/or regional</p><p>wall motion abnormalities may increase the suspicion of ischaemic</p><p>myocardial damage,45 and a pattern of LV dysfunction following the</p><p>theoretical distribution territory of the coronary arteries is typical in</p><p>patients who have already had an MI.46,47 The detection of regional</p><p>wall motion abnormalities can challenging by visual assessment, and</p><p>detection of early systolic lengthening, decreased systolic shortening,</p><p>or post-systolic shortening by strain imaging techniques might be help-</p><p>ful in patients with apparently normal LV function but with clinical sus-</p><p>picion of CCS.48�50 Decreased diastolic LV function has been</p><p>reported to be an early sign of ischaemic myocardial dysfunction and</p><p>could also be indicative of microvascular dysfunction.51,52</p><p>Echocardiography is an important clinical tool for the exclusion of</p><p>alternative causes of chest pain and also aids in diagnosing concurrent</p><p>cardiac diseases, such as valvular heart diseases, HF, and most cardio-</p><p>myopathies,53 but it is important to remember that these diseases</p><p>often coexist with obstructive CAD. The use of an echocardio-</p><p>graphic contrast agent can be useful in patients with poor acoustic</p><p>windows.54</p><p>Cardiac magnetic resonance (CMR) may be considered in</p><p>patients with suspected CAD when the echocardiogram (having</p><p>used contrast) is inconclusive.55 CMR will provide useful informa-</p><p>tion on cardiac anatomy and systolic cardiac function, similar to</p><p>that from an echocardiogram, in patients with no contraindications</p><p>for CMR. CMR can assess global and regional function,56 and the</p><p>use of late gadolinium enhancement CMR can reveal a typical pat-</p><p>tern of scarred myocardium in patients who have already experi-</p><p>enced an MI.57</p><p>Assessment of LV function is important in all patients for risk strati-</p><p>fication (see Supplementary Data section 3.2) and should therefore be</p><p>performed in all symptomatic patients with suspected CAD.</p><p>Resting electrocardiogram in the initial diagnostic man-</p><p>agement of patients with suspected coronary artery</p><p>disease</p><p>Recommendations Classa Levelb</p><p>A resting 12 lead ECG is recommended in all</p><p>patients with chest pain without an obvious</p><p>non-cardiac cause.</p><p>I C</p><p>A resting 12 lead ECG is recommended in all</p><p>patients during or immediately after</p><p>an episode of angina suspected to be indicative</p><p>of clinical instability of CAD.</p><p>I C</p><p>ST-segment alterations recorded during</p><p>supraventricular tachyarrhythmias should not</p><p>be used as evidence of CAD.</p><p>III C</p><p>CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =</p><p>electrocardiogram.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>Ambulatory electrocardiogram monitoring in the initial</p><p>diagnostic management of patients with suspected coro-</p><p>nary artery disease</p><p>Recommendations Classa Levelb</p><p>Ambulatory ECG monitoring is recommended</p><p>in patients with chest pain and</p><p>suspected arrhythmias.</p><p>I C</p><p>Ambulatory ECG recording, preferably moni-</p><p>toring with 12 lead ECG, should be consid-</p><p>ered in patients with suspected vasospastic</p><p>angina.</p><p>IIa C</p><p>Ambulatory ECG monitoring should not be</p><p>used as a routine examination in patients with</p><p>suspected CCS.</p><p>III C</p><p>CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =</p><p>electrocardiogram.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>420 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>Management of patients with either angina or HF symptoms, with</p><p>reduced LVEF</p><p>specific information</p><p>for diagnosis or event risk stratification. The test may occasionally be</p><p>helpful in assessing patients with suspected HF. Chest X-ray may also</p><p>be useful in patients with pulmonary problems, which often accom-</p><p>pany CAD, or to rule-out another cause of chest pain in atypical</p><p>presentations.</p><p>3.1.4 Step 4: Assessment of pre-test probability and clini-</p><p>cal likelihood of coronary artery disease</p><p>The performance of the available methods in diagnosing obstructive</p><p>CAD (i.e. the likelihood that the patient has disease if the test is</p><p>abnormal, and the likelihood that the patient does not have disease if</p><p>the test is normal) depends on the prevalence of disease in the</p><p>population studied and, thus, the likelihood that a given patient will</p><p>actually have CAD. Diagnostic testing is most useful when the likeli-</p><p>hood is intermediate. When likelihood is high, a large number of</p><p>patients need to be studied to identify the few patients that do not</p><p>have disease, and a negative test result can seldom rule out the pres-</p><p>ence of obstructive CAD (i.e. the negative predictive value is low).</p><p>When the likelihood is low, a negative test can rule out the disease,</p><p>but the lower the likelihood, the higher the likelihood of a false-</p><p>positive test (i.e. a positive test in the absence of obstructive CAD).</p><p>In patients at the extreme ends of the probability range, it is therefore</p><p>reasonable to refrain from diagnostic testing, and assume that the</p><p>patient does or does not have obstructive CAD based on clinical</p><p>evaluation alone.</p><p>The likelihood of obstructive CAD is influenced by the prevalence</p><p>of the disease in the population studied, as well as by clinical features</p><p>of an individual patient. A simple predictive model can be used to esti-</p><p>mate the pre-test probability (PTP) of obstructive CAD based on</p><p>age, sex, and the nature of symptoms.59 In the previous version of</p><p>these Guidelines,60 estimation of the PTP was based on data gathered</p><p>by Genders et al.,61 which updated previous data from Diamond and</p><p>Forrester.59 Notably, the prevalence of disease for a given constella-</p><p>tion of age, sex, and nature of symptoms was lower than in</p><p>the Diamond and Forrester data. Since the previous version of the</p><p>Guidelines was published, several studies have indicated that</p><p>the prevalence of obstructive disease among patients with suspected</p><p>CAD is lower than in the previous update.7,8,62,63</p><p>A pooled analysis64 of three contemporary study cohorts, includ-</p><p>ing patients evaluated for suspected CAD,7,8,62 has indicated that the</p><p>PTP based on age, sex, and symptoms is approximately one-third of</p><p>that predicted by the model used in the previous version of the</p><p>Guidelines.57,62 Overestimation of PTP is an important contributory</p><p>factor to a low diagnostic yield of non-invasive and invasive testing.</p><p>The new set of PTPs presented in Table 5 may substantially reduce</p><p>the need for non-invasive and invasive tests in patients with suspected</p><p>stable CAD. The table now also includes patients presenting with</p><p>dyspnoea as their main symptom. However, it should be noted that</p><p>the PTPs presented in Table 5 (as well as the PTP table in the previous</p><p>version of the Guidelines) are based mainly on patients from coun-</p><p>tries with low CVD risk, and may vary between regions and</p><p>countries.</p><p>Application of the new PTPs (Table 5) has important conse-</p><p>quences for the referral of patients for diagnostic testing. If diag-</p><p>nostic testing was deferred in patients with a new PTP</p><p>MI (15%). The regions shaded light green denote the groups with PTPs of CAD between 5�15%, in which</p><p>testing for diagnosis may be considered after assessing the overall clinical likelihood based on the modifiers of PTPs presented in Figure 3.</p><p>422 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>(SPECT), positron emission tomography (PET), myocardial con-</p><p>trast echocardiography, or contrast CMR. Ischaemia can be pro-</p><p>voked by exercise or pharmacological stressors, either by</p><p>increased myocardial work and oxygen demand, or by heteroge-</p><p>neity in myocardial perfusion by vasodilatation. Non-invasive func-</p><p>tional tests are associated with high accuracy for the detection of</p><p>flow-limiting coronary stenosis compared with invasive functional</p><p>testing [fractional flow reserve (FFR)].73 However, lower-grade</p><p>coronary atherosclerosis not linked with ischaemia remains unde-</p><p>tected by functional testing and, in the presence of a negative func-</p><p>tional test, patients should receive risk-factor modification based</p><p>on commonly applied risk charts and recommendations.</p><p>3.1.5.2 Anatomical non-invasive evaluation</p><p>Anatomical non-invasive evaluation, by visualizing the coronary artery</p><p>lumen and wall using an intravenous contrast agent, can be performed</p><p>with coronary CTA, which provides high accuracy for the detection</p><p>of obstructive coronary stenoses defined by ICA,73 because both tests</p><p>are based on anatomy. However, stenoses estimated to be 50�90%</p><p>by visual inspection are not necessarily functionally significant, i.e. they</p><p>do not always induce myocardial ischaemia.73,74 Therefore, either</p><p>non-invasive or invasive functional testing is recommended for further</p><p>evaluation of angiographic stenosis detected by coronary CTA or</p><p>invasive angiography, unless a very high-grade (>90% diameter steno-</p><p>sis) stenosis is detected via invasive angiography. The presence or</p><p>absence of non-obstructive coronary atherosclerosis on coronary</p><p>CTA provides prognostic information, and can be used to guide pre-</p><p>ventive therapy.75 The SCOT-HEART (Scottish Computed</p><p>Tomography of the HEART) trial demonstrated a significantly lower</p><p>rate of the combined endpoint of cardiovascular death or non-fatal MI</p><p>(2.3 vs. 3.9% during 5 year follow-up) in patients in whom coronary</p><p>CTA was performed in addition to routine testing, which consisted</p><p>predominantly of exercise ECG.6 Other randomized, prospective clin-</p><p>ical trials have demonstrated that diagnostic testing with coronary</p><p>CTA is associated with clinical outcomes similar to those for func-</p><p>tional imaging in patients with suspected CAD.4,6,76 In patients with</p><p>extensive CAD, coronary CTA complemented by CT-based FFR was</p><p>non-inferior to ICA and FFR for decision-making, and the identification</p><p>of targets for revascularization.77</p><p>3.1.5.3 Role of the exercise electrocardiogram</p><p>Exercise ECG has inferior diagnostic performance compared with</p><p>diagnostic imaging tests, and has limited power to rule-in or rule-out</p><p>obstructive CAD.73 Since the publication of the previous version of</p><p>these Guidelines, randomized clinical trials (RCTs) have compared</p><p>the effects of diagnostic strategies based on exercise ECG or an imag-</p><p>ing diagnostic test6,78,79 on clinical outcomes. These studies have</p><p>shown that the addition of coronary CTA5,6,78,80 or functional</p><p>imaging79 clarifies the diagnosis, enables the targeting of preventive</p><p>therapies and interventions, and potentially reduces the risk of MI</p><p>compared with an exercise ECG. Some, although not all, registry</p><p>studies have also shown similar benefits regarding the use of an imag-</p><p>ing diagnostic test in patients treated in everyday clinical practice.81,82</p><p>Therefore, these Guidelines recommend the use of an imaging diag-</p><p>nostic test instead of exercise ECG as the initial test for to diagnose</p><p>obstructive CAD.</p><p>An exercise ECG alone may be considered as an alternative to</p><p>diagnose obstructive CAD if imaging tests are not available, keeping</p><p>in mind the risk of false-negative and false-positive test results.73,83</p><p>An exercise ECG is of no diagnostic value in patients with ECG</p><p>abnormalities that prevent interpretation of the ST-segment changes</p><p>during stress (i.e. LBBB, paced rhythm, Wolff-Parkinson-White syn-</p><p>drome, >_0.1 mV ST-segment depression on resting ECG, or who are</p><p>being treated with digitalis). An exercise ECG provides</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>PTP based on sex, age and nature of symptoms (Table 5)</p><p>Clinical likelihood of CAD</p><p>Decreases likelihood</p><p>• Normal exercise ECGa</p><p>• No coronary calcium by CT</p><p>(Agatston score = 0)a</p><p>Increases likelihood</p><p>• Risk factors for CVD</p><p>(dyslipidaemia, diabetes,</p><p>hypertension, smoking,</p><p>family history of CVD)</p><p>• Resting ECG changes</p><p>(Q-wave or ST-segment/</p><p>T-wave changes)</p><p>• LV dysfunction suggestive</p><p>of CAD</p><p>• Abnormal exercise ECGa</p><p>• Coronary calcium by CTa</p><p>Figure 3 Determinants of the clinical likelihood of obstructive coronary artery disease. CAD = coronary artery disease; CT = computed tomography,</p><p>CVD = cardiovascular disease, ECG = electrocardiogram, LV = left ventricular; PTP = pre-test probability. aWhen available.</p><p>ESC Guidelines 423</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..complementary clinically useful information beyond ECG changes</p><p>and valuable prognostic information. Therefore, application of an</p><p>exercise ECG may be considered in selected patients to complement</p><p>clinical evaluation for the assessment of symptoms, ST-segment</p><p>changes, exercise tolerance, arrhythmias, blood pressure (BP)</p><p>response, and event risk.</p><p>3.1.5.4 Selection of diagnostic tests</p><p>Either a functional or anatomical test can be used to establish a diag-</p><p>nosis of obstructive CAD. A summary of the main diagnostic path-</p><p>ways is displayed in Figure 4. For revascularization decisions,</p><p>information on both anatomy and ischaemia is needed.</p><p>3.1.5.5 The impact of clinical likelihood on the selection of a diagnostic test</p><p>Each non-invasive diagnostic test has a particular range of clinical like-</p><p>lihood of obstructive CAD where the usefulness of its application is</p><p>maximal. The likelihood ratios of the tests constitute useful parame-</p><p>ters of their abilities to correctly classify patients, and can be used to</p><p>facilitate the selection of the most useful test in any given patient.73,84</p><p>Given a clinical likelihood of obstructive CAD and the likelihood ratio</p><p>of a particular test, one can assess the post-test probability of</p><p>obstructive CAD after performing such a test. Using this approach,</p><p>one can estimate the optimal ranges of clinical likelihood for each</p><p>test, where they can reclassify patients from intermediate to either</p><p>low or high post-test probability of CAD (Figure 5).73</p><p>Coronary CTA is the preferred test in patients with a lower range</p><p>of clinical likelihood of CAD, no previous diagnosis of CAD, and</p><p>characteristics associated with a high likelihood of good image quality.</p><p>It detects subclinical coronary atherosclerosis, but can also accu-</p><p>rately rule out both anatomically and functionally significant CAD</p><p>(Figure 5). It has higher accuracy values when low clinical likelihood</p><p>populations are subjected to examination.85 Trials evaluating out-</p><p>comes after coronary CTA to date have mostly included patients</p><p>with a low clinical likelihood.4,5</p><p>The non-invasive functional tests for ischaemia typically have bet-</p><p>ter rule-in power. In outcome trials, functional imaging tests have</p><p>been associated with fewer referrals for downstream ICA compared</p><p>with a strategy relying on anatomical imaging.55,76,86 Before revascula-</p><p>rization decisions can be made, functional evaluation of ischaemia</p><p>(either non-invasive or invasive) is required in most patients.</p><p>Therefore, functional non-invasive testing may be preferred in</p><p>patients at the higher end of the range of clinical likelihood if revascu-</p><p>larization is likely or the patient has previously diagnosed CAD.</p><p>Patients in whom CAD is suspected, but who have a very low clini-</p><p>cal likelihood (90%</p><p>or with established</p><p>correlation to ischaemia</p><p>Figure 4 Main diagnostic pathways in symptomatic patients with suspected obstructive coronary artery disease. Depending on clinical conditions and</p><p>the healthcare environment, patient workup can start with either of three options: non-invasive testing, coronary computed tomography angiography, or</p><p>invasive coronary angiography. Through each pathway, both functional and anatomical information is gathered to inform an appropriate diagnostic and</p><p>therapeutic strategy. Risk-factor modification should be considered in all patients. CAD = coronary artery disease; CTA = computed tomography angiog-</p><p>raphy; ECG = electrocardiogram; LV = left ventricular. aConsider microvascular angina. bAntianginal medications and/or risk-factor modification.</p><p>424 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..In addition to diagnostic accuracy and clinical likelihood, the selec-</p><p>tion of a non-invasive test depends on other patient characteristics,</p><p>local expertise, and the availability of tests. Some diagnostic tests may</p><p>perform better in some patients than others. For example, irregular</p><p>heart rate and the presence of extensive coronary calcification are</p><p>associated with increased likelihood of non-diagnostic image quality</p><p>of coronary CTA, and it is not recommended in such patients.85</p><p>Stress echocardiography or SPECT perfusion imaging can be com-</p><p>bined with dynamic exercise testing, and may be preferred if addi-</p><p>tional information available from the exercise test, such as exercise</p><p>tolerance or heart rate response to exercise, is considered impor-</p><p>tant. Exercise ECG cannot be used for diagnostic purposes in the</p><p>presence of ECG abnormalities that prevent the evaluation of ischae-</p><p>mia. Risks related to different diagnostic tests need to be weighed</p><p>against the benefits to the individual.87 For example, exposure to ion-</p><p>izing radiation associated with coronary CTA and nuclear perfusion</p><p>imaging needs to be taken into account, especially in young individu-</p><p>als.87 Similarly, contraindications to pharmacological stressors and</p><p>contrast agents (iodine-based contrast agents and gadolinium-based</p><p>chelates) need to be taken into account. When testing is used appro-</p><p>priately, the clinical benefit from accurate diagnosis and therapy</p><p>exceeds the projected risks of testing itself.87</p><p>3.1.5.6 Invasive testing</p><p>For diagnostic purposes, ICA is only necessary in patients with sus-</p><p>pected CAD in cases of inconclusive non-invasive testing or, exception-</p><p>ally, in patients from particular professions, due to regulatory issues.88</p><p>However, ICA may be indicated if non-invasive assessment suggests</p><p>high event risk for determination of options for revascularization.88</p><p>In a patient with a high clinical likelihood of CAD, and symptoms</p><p>unresponsive to medical therapy or with typical angina at a low level</p><p>of exercise, and initial clinical evaluation indicates a high event risk,</p><p>early ICA without previous non-invasive risk stratification may be</p><p>reasonable to identify lesions potentially amenable to revasculariza-</p><p>tion (Figure 4). Invasive functional assessment should complement</p><p>ICA, especially in patients with coronary stenoses of 50 - 90% or mul-</p><p>tivessel disease, given the</p><p>frequent mismatch between the angio-</p><p>graphic and haemodynamic severities of coronary stenoses.89�91</p><p>Systematic integration of ICA with FFR has been shown to result in</p><p>changes to the management strategies of 30 - 50% of patients under-</p><p>going elective ICA.92,93 Methods used to perform ICA have improved</p><p>substantially, resulting in a reduction of complication rates with rapid</p><p>ambulation. This is especially true for ICA performed via the radial</p><p>artery.94 The composite rate of major complications associated with</p><p>routine femoral diagnostic catheterization—mainly bleeding requir-</p><p>ing blood transfusions—is still 0.5�2%.95 The composite rate of</p><p>death, MI, or stroke is of the order of 0.1�0.2%.96 ICA should not be</p><p>performed in patients with angina who refuse invasive procedures,</p><p>prefer to avoid revascularization, who are not candidates for percuta-</p><p>neous coronary intervention (PCI) or coronary artery bypass grafting</p><p>(CABG), or in whom revascularization is not expected to improve</p><p>functional status or quality of life. Intracoronary techniques for the</p><p>diagnostic assessment of coronary anatomy are briefly mentioned in</p><p>the Supplementary Data of this document.</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>Test</p><p>Results</p><p>Stress ECG</p><p>Coronary CTA</p><p>Stress</p><p>CMR</p><p>SPECT</p><p>Stress</p><p>Echocardiography</p><p>PET</p><p>A Test</p><p>Results</p><p>ICA</p><p>Coronary CTA</p><p>Stress</p><p>CMR</p><p>SPECT</p><p>Clinical Likelihood range where test</p><p>can rule-in CAD (Post-test probability will rise above 85%)</p><p>Clinical Likelihood range where test</p><p>can rule-out CAD (Post-test probability will rise below 15%)</p><p>PET</p><p>BClinical Likelihood of ICA-significant CAD</p><p>0%</p><p>15% 85%</p><p>100%50%</p><p>Clinical Likelihood of FFR-significant CAD</p><p>0%</p><p>15% 85%</p><p>100%50%</p><p>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</p><p>artery disease. (A) Reference standard is anatomical assessment using invasive coronary angiography. (B) Reference standard is functional assess-</p><p>ment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are</p><p>more limited than with the other techniques.73 The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from</p><p>Knuuti et al.73 CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocar-</p><p>diogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emis-</p><p>sion computed tomography.</p><p>ESC Guidelines 425</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected coronary</p><p>artery disease</p><p>Recommendations Classa Levelb</p><p>Non-invasive functional imaging for myocardial ischaemiac or coronary CTA is recommended as the initial test to diagnose</p><p>CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.4,5,55,73,78�80 I B</p><p>It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD</p><p>and other patient characteristics that influence test performance,d local expertise, and the availability of tests.</p><p>I C</p><p>Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-</p><p>nificance or is not diagnostic.4,55,73 I B</p><p>Invasive coronary angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likeli-</p><p>hood, severe symptoms refractory to medical therapy or typical angina at a low level of exercise, and clinical evaluation</p><p>that indicates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revas-</p><p>cularization, unless very high grade (>90% diameter stenosis).71,72,74</p><p>I B</p><p>Invasive coronary angiography with the availability of invasive functional evaluation should be considered for confirmation</p><p>of the diagnosis of CAD in patients with an uncertain diagnosis on non-invasive testing.71,72 IIa B</p><p>Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or</p><p>non-diagnostic.</p><p>IIa C</p><p>Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inabil-</p><p>ity to cooperate with breath-hold commands, or any other conditions make obtaining good image quality unlikely.</p><p>III C</p><p>Coronary calcium detection by CT is not recommended to identify individuals with obstructive CAD. III C</p><p>CAD = coronary artery disease; CT = computed tomography; CTA = computed tomography angiography.</p><p>aClass of recommendation.</p><p>bLevel of evidence</p><p>cStress echocardiography, stress cardiac magnetic resonance, single-photon emission CT, or positron emission tomography.</p><p>dCharacteristics determining ability to exercise, likelihood of good image quality, expected radiation exposure, and risks or contraindications.</p><p>Use of exercise electrocardiogram in the initial diagnostic management of patients with suspected coronary artery</p><p>disease</p><p>Recommendations Classa Levelb</p><p>Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event</p><p>risk in selected patients.c</p><p>I C</p><p>Exercise ECG may be considered as an alternative test to rule-in and rule-out CAD when non-invasive imaging is not</p><p>available.73,83 IIb B</p><p>Exercise ECG may be considered in patients on treatment to evaluate control of symptoms and ischaemia. IIb C</p><p>Exercise ECG is not recommended for diagnostic purposes in patients with >_0.1 mV ST-segment depression on resting</p><p>ECG or who are being treated with digitalis.</p><p>III C</p><p>BP = blood pressure; CAD = coronary artery disease; ECG = electrocardiogram.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>cWhen this information will have an impact on diagnostic strategy or management.</p><p>426 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..3.1.6 Step 6: Assessment of event risk</p><p>Assessment of event risk is recommended in every patient being eval-</p><p>uated for suspected CAD or with a newly diagnosed CAD, as it has</p><p>major impacts on therapy decisions. The process of risk stratification</p><p>serves to identify patients at high event risk who will benefit from</p><p>revascularization beyond the amelioration of symptoms. Event risk</p><p>stratification is usually based on the assessments used to make a diag-</p><p>nosis of CAD. All patients should undergo cardiovascular event risk</p><p>stratification using clinical evaluation, the assessment of LV function by</p><p>resting echocardiography, and, in the majority of cases, non-invasive</p><p>assessment of ischaemia or coronary anatomy. Although the diagnos-</p><p>tic value of an exercise ECG is limited,73 the occurrence of ST-</p><p>segment depression at a low workload combined with exertional</p><p>symptoms (angina or dyspnoea), low exercise capacity, complex ven-</p><p>tricular ectopy, or arrhythmias and abnormal BP response are</p><p>markers of a high risk of cardiac mortality.97�100 Patients with typical</p><p>Table 6 Definitions of high event risk for different test modalities in patients with established chronic coronary syndro-</p><p>mesa 102�104</p><p>Exercise ECG Cardiovascular mortality >3% per year according to Duke Treadmill Score</p><p>SPECT or PET perfusion imaging Area of ischaemia >_10% of the left ventricle myocardium</p><p>Stress echocardiography >_3 of 16 segments with stress-induced hypokinesia or akinesia</p><p>CMR >_2 of 16 segments with stress perfusion defects or >_3 dobutamine-induced dysfunctional segments</p><p>Coronary CTA or ICA Three-vessel disease with proximal stenoses, LM disease, or proximal anterior descending disease</p><p>Invasive functional testing FFR</p><p>= cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;</p><p>iwFR = instantaneous wave-free ration (instant flow reserve); LM = left main; PET = positron emission tomography; SPECT; single-photon emission computed tomography.</p><p>aFor detailed explanations, refer to the Supplementary Data.</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>15% and over</p><p>10%–14%</p><p>5%–9%</p><p>3%–4%</p><p>2%</p><p>1%</p><p>3%</p><p>per year and low event risk as a cardiac mortality rate 35%.110�114 IIb B</p><p>Intravascular ultrasound may be considered for the risk stratification of patients with intermediate LM stenosis.115,116 IIb B</p><p>ICA is not recommended solely for risk stratification. III C</p><p>CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;</p><p>iwFR = instantaneous wave-free ratio; LM = left main; LV = left ventricular; LVEF = LV ejection fraction.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>428 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>3.2 Lifestyle management</p><p>3.2.1 General management of patients with coronary</p><p>artery disease</p><p>General management of CCS aims to reduce symptoms and</p><p>improve prognosis through appropriate medications and inter-</p><p>ventions, and to control risk factors including lifestyle behaviours.</p><p>Optimal medical therapy in the COURAGE (Clinical Outcomes</p><p>Utilizing Revascularization and Aggressive Drug Evaluation) trial</p><p>included the promotion of medication adherence, behavioural</p><p>counselling, and support for the managing lifestyle risk factors</p><p>delivered by nurse case managers.117 Achievement of optimal</p><p>management may be best accomplished through a multidiscipli-</p><p>nary team approach that can provide tailored and flexible support</p><p>to patients.</p><p>Patient-reported outcome measures can provide relevant and</p><p>systematic information about patients’ symptoms, functioning, and</p><p>concerns. Patient-reported outcome measures are increasingly</p><p>being implemented sequentially in healthcare, and have been</p><p>shown to improve clinical care and patient experiences, communi-</p><p>cation between providers and patients (including sensitive sub-</p><p>jects), save time in consultations, and improve provider</p><p>satisfaction.118</p><p>3.2.2 Lifestyle modification and control of risk factors</p><p>Implementing healthy lifestyle behaviours decreases the risk of subse-</p><p>quent cardiovascular events and mortality, and is additional to appro-</p><p>priate secondary prevention therapy. Lifestyle recommendations and</p><p>interventions are described in more detail in the 2016 ESC</p><p>Guidelines on CVD prevention in clinical practice.15 Lifestyle factors</p><p>are important and the implementation of healthy behaviours (includ-</p><p>ing smoking cessation, recommended physical activity, a healthy diet,</p><p>and maintaining a healthy weight; see Table 7) significantly decreases</p><p>the risk of future cardiovascular events and death, even when con-</p><p>trolling for evidence-based secondary prevention therapy and inter-</p><p>ventions.119�122 Benefits are evident as early as 6 months after</p><p>an</p><p>index event.119</p><p>Primary care providers have an important role to play in preven-</p><p>tion. The primary care arm of the EUROACTION cluster random-</p><p>ized trial demonstrated that a nurse-co-ordinated programme in</p><p>primary care was more effective in helping patients achieve lifestyle</p><p>and risk-factor goals than usual care.123 Practice nurses in the</p><p>Netherlands were found to be as effective as general practitioners in</p><p>decreasing cardiovascular risk in another randomized study.123</p><p>3.2.2.1 Smoking</p><p>Smoking cessation improves the prognosis in patients with CCS,</p><p>including a 36% risk reduction in mortality for those who quit.124</p><p>Measures to promote smoking cessation include brief advice, coun-</p><p>selling and behavioural interventions, and pharmacological therapy</p><p>including nicotine replacement. Patients should also avoid passive</p><p>smoking.</p><p>Brief advice, relative to no treatment, doubles the likelihood of</p><p>smoking cessation in the short-term, but more intensive advice and</p><p>support (behavioural interventions, telephone support, or self-help</p><p>measures) is more effective than brief advice, especially if continued</p><p>over 1 month.125,126 All forms of nicotine-replacement therapy,</p><p>bupropion, and varenicline are more effective in increasing smoking</p><p>cessation than control, and combining behavioural and pharmacologi-</p><p>cal approaches is effective and highly recommended.125 A network</p><p>meta-analysis of 63 clinical trials (including eight trials in CVD</p><p>patients) found no increase in major adverse cardiovascular events</p><p>linked to nicotine-replacement therapy, bupropion, or varenicline.127</p><p>Nicotine-replacement therapy was associated with minor events</p><p>such as arrhythmias and angina, and bupropion appeared to have a</p><p>protective effect against major adverse cardiovascular events.127 The</p><p>use of e-cigarettes is considered to be a reduced-harm alternative to</p><p>conventional cigarettes, but they are not harm-free. Newer devices</p><p>can deliver higher nicotine contents, and e-cigarettes emit other con-</p><p>stituents such as carbonyls and fine and ultrafine particulates.128</p><p>Although previous systematic reviews have found very limited and</p><p>inconsistent evidence that e-cigarettes (primarily first-generation</p><p>devices) are useful in improve smoking cessation compared with pla-</p><p>cebo or nicotine-replacement therapy, a recent large clinical trial</p><p>found e-cigarettes to be more effective than nicotine-replacement</p><p>therapy in smoking cessation.129�133 In this randomised trial of 886</p><p>smokers, those assigned to e-cigarettes had a sustained 1 year absti-</p><p>nence rate of 18% compared with 9.9% for nicotine-replacement</p><p>therapy [relative risk, 1.83; 95% confidence interval (CI) 1.30 to 2.58;</p><p>P 100 g</p><p>per week were associated with higher all-cause and other CVD</p><p>mortality in a large individual-data meta-analysis.139 The Global</p><p>Burden of Disease 1990�2016 analysis concluded that zero alco-</p><p>hol intake was the level at which risk for death and disability was</p><p>minimized.140</p><p>3.2.2.3 Weight management</p><p>In a population-based study, lifetime risk of incident CVD, and car-</p><p>diovascular morbidity and mortality, were higher in those who</p><p>were overweight or obese compared with those with a normal</p><p>BMI (20 - 25 kg/m2). Obesity was associated with a shorter overall</p><p>lifespan, and overweight was associated with developing CVD at</p><p>an earlier age.143 Waist circumference is a marker of central obe-</p><p>sity and is strongly associated with developing CVD and diabetes.</p><p>Waist circumference _5 days per</p><p>week.147 Even irregular leisure-time physical activity decreases mortal-</p><p>ity risk among previously sedentary patients,149 and increasing activity</p><p>is associated with lower cardiovascular mortality.150 Previously seden-</p><p>tary patients will need support to work up to 30�60 min most days,</p><p>reassurance that exercise is beneficial, and education regarding what</p><p>to do if angina occurs while being active. Resistance exercises maintain</p><p>muscle mass, strength, and function and, with aerobic activity, have</p><p>benefits regarding insulin sensitivity and control of lipids and BP.</p><p>3.2.2.5 Cardiac rehabilitation</p><p>Exercise-based cardiac rehabilitation has consistently demonstrated</p><p>its effectiveness in reducing cardiovascular mortality and hospitaliza-</p><p>tions compared with no exercise controls in patients with CAD, and</p><p>this benefit persists into the modern era.151�153 Most patients partici-</p><p>pating in cardiac rehabilitation are referred following an acute MI or</p><p>after revascularization, with 0 - 24% of patients found to be referred</p><p>for CCS in 12 European countries.154 Importantly,</p><p>the benefits of car-</p><p>diac rehabilitation occur across diagnostic categories.151�153</p><p>3.2.2.6 Psychosocial factors</p><p>Patients with heart disease have a two-fold increased risk of mood</p><p>and anxiety disorders compared with people without heart dis-</p><p>ease.155,156 Psychosocial stress, depression, and anxiety are associ-</p><p>ated with worse outcomes, and make it difficult for patients to make</p><p>positive changes to their lifestyles or adhere to a therapeutic regimen.</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>Assist with</p><p>smoking</p><p>cessation</p><p>Arrange</p><p>follow-up</p><p>Advise to</p><p>quit</p><p>Assess</p><p>readiness</p><p>to quit</p><p>Ask about</p><p>smoking</p><p>5As</p><p>Figure 7 The five As of smoking cessation.</p><p>Table 8 Healthy diet characteristics134,137,141,142</p><p>Characteristics</p><p>Increase consumption of fruits and vegetables (>_200 g each per day).</p><p>35�45 g of fibre per day, preferably from wholegrains.</p><p>Moderate consumption of nuts (30 g per day, unsalted).</p><p>1�2 servings of fish per week (one to be oily fish).</p><p>Limited lean meat, low-fat dairy products, and liquid vegetable oils.</p><p>Saturated fats to account for _65 years.178�180 Therefore,</p><p>annual influenza vaccination is recommended for patients with CAD,</p><p>especially in the elderly.</p><p>Recommendations on lifestyle management</p><p>Recommendations Classa Levelb</p><p>Improvement of lifestyle factors in addition</p><p>to appropriate pharmacological management is</p><p>recommended.119�122,124,148�153</p><p>I A</p><p>Cognitive behavioural interventions are rec-</p><p>ommended to help individuals achieve a</p><p>healthy lifestyle.181�183</p><p>I A</p><p>Exercise-based cardiac rehabilitation is recom-</p><p>mended as an effective means for patients</p><p>with CCS to achieve a healthy lifestyle and</p><p>manage risk factors.151�153</p><p>I A</p><p>Involvement of multidisciplinary healthcare pro-</p><p>fessionals (e.g. cardiologists, GPs, nurses, dieti-</p><p>cians, physiotherapists, psychologists, and</p><p>pharmacists) is recommended.121,123,181,184</p><p>I A</p><p>Psychological interventions are recommended</p><p>to improve symptoms of depression in</p><p>patients with CCS.126,157</p><p>I B</p><p>Annual influenza vaccination is recommended</p><p>for patients with CCS, especially in the</p><p>elderly.175,176,178,179,185�187</p><p>I B</p><p>CCS = chronic coronary syndrome; GPs = general practitioners.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>ESC Guidelines 431</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>3.3 Pharmacological management</p><p>The aims of pharmacological management of CCS patients are to</p><p>reduce angina symptoms and exercise-induced ischaemia, and to pre-</p><p>vent cardiovascular events.</p><p>Immediate relief of anginal symptoms, or the prevention of symp-</p><p>toms under circumstances likely to elicit angina, is usually obtained</p><p>with rapidly acting formulations of nitroglycerin. Anti-ischaemic</p><p>drugs—but also lifestyle changes, regular exercise training, patient</p><p>education, and revascularization—all play a role in minimizing or</p><p>eradicating symptoms over the long-term (long-term prevention).</p><p>Prevention of cardiovascular events targets MI and death associ-</p><p>ated with CAD, and focuses primarily on reducing the incidence of</p><p>acute thrombotic events and the development of ventricular dysfunc-</p><p>tion. Strategies include pharmacological and lifestyle interventions, as</p><p>detailed in the 2016 European Guidelines on CVD prevention in clini-</p><p>cal practice.15</p><p>3.3.1 Anti-ischaemic drugs</p><p>3.3.1.1 General strategy</p><p>Optimal treatment can be defined as the treatment that satisfactorily</p><p>controls symptoms and prevents cardiac events associated with CCS,</p><p>with maximal patient adherence and minimal adverse events.188�191</p><p>However, there is no universal definition of an optimal treatment in</p><p>patients with CCS, and drug therapies must be adapted to each</p><p>patient’s characteristics and preferences.192 Initial drug therapy usually</p><p>consists of one or two antianginal drugs, as necessary, plus drugs for</p><p>secondary prevention of CVD.193 The initial choice of antianginal</p><p>drug(s) depends on the expected tolerance related to the individual</p><p>patient’s profile and comorbidities, potential drug interactions with co-</p><p>administered therapies, the patient’s preferences after being informed</p><p>of potential adverse effects, and drug availability. Whether combination</p><p>therapy with two antianginal drugs [e.g. a beta-blocker and a calcium</p><p>channel blocker (CCB)] is superior to monotherapy with any class of</p><p>antianginal drug in reducing clinical events remains unclear.194�197</p><p>Beta-adrenergic blockers or CCBs are recommended as the first</p><p>choice, although no RCT to date has compared this strategy to an</p><p>alternative strategy using initial prescription of other anti-ischaemic</p><p>drugs, or the combination of a beta-blocker and a CCB.191,195 The</p><p>results of a network meta-analysis of 46 studies and 71 treatment com-</p><p>parisons supported the initial combination of a beta-blocker and a</p><p>CCB.198 The same meta-analysis suggested that several second-line</p><p>add-on anti-ischaemic drugs (long-acting nitrates, ranolazine, trimetazi-</p><p>dine, and, to a lesser extent, ivabradine) may prove beneficial in combi-</p><p>nation with a beta-blocker or a CCB as first-line therapy, while no data</p><p>were available for nicorandil. However, it should be noted that the</p><p>study pooled RCTs using endpoints of nitrate use, angina frequency,</p><p>time to angina or to ST-segment depression, and total exercise time,</p><p>and no study or meta-analysis has yet assessed with sufficient power</p><p>the influence of combining a beta-blocker or a CCB with a second-line</p><p>anti-ischaemic drug on morbidity or mortality events.198 Regardless of</p><p>the initial strategy, response to initial antianginal therapy should be</p><p>reassessed after 2�4 weeks of treatment initiation.</p><p>3.3.1.2 Available drugs</p><p>Anti-ischaemic drugs have proved benefits regarding symptoms asso-</p><p>ciated with myocardial ischaemia but do not prevent cardiovascular</p><p>events in most patients with CCS. Supplementary Table 3 in the</p><p>Supplementary Data summarizes the principal major side effects,</p><p>contraindications, drug�drug interactions, and precautions relating</p><p>to anti-ischaemic drugs. Supplementary Table 2 summarizes the main</p><p>mechanisms of action of anti-ischaemic drugs.</p><p>3.3.1.2.1 Nitrates.</p><p>Short-acting nitrates for acute effort angina</p><p>Sublingual and spray nitroglycerin formulations provide immediate</p><p>relief of effort angina. Spray nitroglycerin acts more rapidly than sub-</p><p>lingual nitroglycerin.199 At the onset of angina symptoms, the patient</p><p>should rest in a sitting position (standing promotes syncope, and lying</p><p>down enhances venous return and preload) and take nitroglycerin</p><p>(0.3�0.6 mg tablet sublingually and not swallowed, or 0.4 mg spray</p><p>to the tongue and not swallowed or inhaled) every 5 min until the</p><p>pain disappears, or a maximum of 1.2 mg has been taken within 15</p><p>min. During this time frame, if angina persists, immediate medical</p><p>attention is needed. Nitroglycerin can be administered for prophy-</p><p>laxis before physical activities known to provoke angina. Isosorbide</p><p>dinitrate (5 mg sublingually) has a slightly slower onset of action than</p><p>nitroglycerin due to hepatic conversion to mononitrate. The effect of</p><p>isosorbide dinitrate may last</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>vasoconstriction, postural hypotension, impotence, and masking of</p><p>hypoglycaemia symptoms.</p><p>In certain patients with recent MI and those with chronic HF with</p><p>reduced ejection fraction, beta-blockers have been associated with a</p><p>significant reduction in mortality and/or cardiovascular events,209�215</p><p>but the protective benefit in patients with CAD without prior MI or</p><p>HF is less well established and lacks placebo-controlled trials.216 A</p><p>retrospective analysis of 21 860 matched patients from the REACH</p><p>(REduction of Atherothrombosis for Continued Health) Registry</p><p>showed no reduction in cardiovascular mortality with beta-blockers</p><p>in patients with either CAD with risk factors only, known prior MI, or</p><p>known CAD without MI.217 In a retrospective national registry of</p><p>755 215 patients aged >_65 years with a history of CAD without prior</p><p>MI or HF with reduced ejection fraction undergoing elective PCI,</p><p>beta-blocker use at discharge was not associated with any reduction</p><p>in cardiovascular morbidity or mortality at 30 day and 3 year follow-</p><p>up.218 However, in patients with or without previous MI undergoing</p><p>CABG, beta-blockers were associated with lower risk of long-term</p><p>mortality and adverse cardiovascular events.219 Other observational</p><p>studies and meta-analyses have questioned the benefit of long-term</p><p>(>1 year) beta-blocker therapy in patients with a previous</p><p>MI.216,220�224 This is still a matter for debate,225 and uncertainties</p><p>remain on the comparative role of beta-blockers and angiotensin-</p><p>converting enzyme (ACE) inhibitors.</p><p>3.3.1.2.3 Calcium channel blockers. While CCBs improve symptoms</p><p>and myocardial ischaemia, they have not been shown to reduce</p><p>major morbidity endpoints or mortality in patients with</p><p>CCS.192,226�228</p><p>NON-DIHYDROPYRIDINE AGENTS (HEART RATE-LOWERING CALCIUM CHANNEL</p><p>BLOCKERS)</p><p>Verapamil. Verapamil has a large range of approved indications,</p><p>including all varieties of angina (effort, vasospastic, and unstable),</p><p>supraventricular tachycardias, and hypertension. Indirect evidence</p><p>suggests good safety but with risks of heart block, bradycardia, and</p><p>HF. Compared with metoprolol, the antianginal activity was simi-</p><p>lar.229 Compared with atenonol in hypertension with CAD, verapa-</p><p>mil is associated with fewer cases of diabetes, fewer anginal</p><p>attacks,230 and less psychological depression.231 Beta-blockade com-</p><p>bined with verapamil is not advised (due to risk of heart block).</p><p>Diltiazem. Diltiazem, with its low-side effect profile, has advantages</p><p>compared with verapamil in the treatment of effort angina. Like vera-</p><p>pamil, it acts by peripheral vasodilation, relief of exercise-induced</p><p>coronary constriction, a modest negative inotropic effect, and sinus</p><p>node inhibition. There have been no outcome studies comparing dil-</p><p>tiazem and verapamil.</p><p>In some selected patients, non-DHP agents may be combined with</p><p>beta-blockers for the treatment of angina. However, on such occa-</p><p>sions they must be used under close monitoring of patients’ tolerance</p><p>regarding excessive bradycardia or signs of HF. Use of non-DHP</p><p>CCBs in patients with LV dysfunction is not advised.</p><p>DIHYDROPYRIDINE AGENTS</p><p>Long-acting nifedipine. This agent is a powerful arterial vasodilator with</p><p>few serious side effects. Long-acting nifedipine has been especially</p><p>well tested in hypertensive anginal patients when added to beta-</p><p>blockade.232 In the large placebo-controlled ACTION (A Coronary</p><p>disease Trial Investigating Outcome with Nifedipine gastrointestinal</p><p>therapeutic system) trial, addition of long-acting nifedipine [60 mg</p><p>o.d. (once a day)] to conventional treatment of angina had no effect</p><p>on major cardiovascular event-free survival. Long-acting nifedipine</p><p>proved to be safe, and reduced the need for coronary angiography</p><p>and cardiovascular interventions.232 Relative contraindications to</p><p>nifedipine are few (severe aortic stenosis, hypertrophic obstructive</p><p>cardiomyopathy, or HF), and careful combination with beta-blockade</p><p>is usually feasible and desirable. Vasodilatory side effects include</p><p>headache and ankle oedema.</p><p>Amlodipine. The very long half-life of amlodipine and its good toler-</p><p>ability make it an effective once-a-day antianginal and antihyperten-</p><p>sive agent, setting it apart from drugs that are taken either twice or</p><p>three times daily. Side effects are few, mainly ankle oedema. In</p><p>patients with CCS and normal BP (�75% receiving a beta-blocker),</p><p>amlodipine 10 mg/day reduced coronary revascularizations and hos-</p><p>pitalizations for angina in a 24 month trial.233 Exercise-induced ischae-</p><p>mia is more effectively reduced by amlodipine, 5 mg titrated to</p><p>10 mg/day, than by the beta-blocker atenolol, 50 mg/day, and their</p><p>combination is even better.234 However, the CCB�beta-blocker</p><p>combination is often underused, even in some studies reporting ‘opti-</p><p>mally treated’ stable effort angina.</p><p>3.3.1.2.4 Ivabradine. Ivabradine has been reported to be non-inferior</p><p>to atenolol or amlodipine in the treatment of angina and ischaemia in</p><p>patients with CCS.235,236 Adding ivabradine 7.5 mg b.i.d. [bis in die</p><p>(twice a day)] to atenolol therapy gave better control of heart rate</p><p>and anginal symptoms.237 In 10 917 patients with limiting previous</p><p>angina enrolled in the morbidity�mortality evaluation of the</p><p>BEAUTIFUL (If Inhibitor Ivabradine in Patients With Coronary Artery</p><p>Disease and Left Ventricular Dysfunction) trial, ivabradine did not</p><p>reduce the composite primary endpoint of cardiovascular death, hos-</p><p>pitalization with MI, or HF.238 Also, in the SIGNIFY (Study Assessing</p><p>the Morbidity�Mortality Benefits of the If Inhibitor Ivabradine in</p><p>Patients with Coronary Artery Disease) study, consisting of 19 102</p><p>patients with CAD without clinical HF and a heart rate >_70 b.p.m.,</p><p>there was no significant difference between the ivabradine group and</p><p>the placebo group in the incidence of the primary composite end-</p><p>point of death from cardiovascular causes or non-fatal MI.239</p><p>Ivabradine was associated with an increase in the incidence of the pri-</p><p>mary endpoint among 12 049 patients with activity-limiting angina but</p><p>not among those without activity-limiting angina (P=0.02 for interac-</p><p>tion). In 2014, the European Medicines Agency issued recommenda-</p><p>tions to reduce the risk of bradycardia and placed ivabradine under</p><p>additional monitoring.240 In aggregate, these results support the use</p><p>of ivabradine as a second-line drug in patients with CCS.</p><p>3.3.1.2.5 Nicorandil. Nicorandil is a nitrate derivative of nicotinamide,</p><p>with antianginal effects similar to those of nitrates or beta-block-</p><p>ers.241�244 Side effects include nausea, vomiting, and potentially</p><p>severe oral, intestinal, and mucosal ulcerations.245</p><p>In the placebo-controlled IONA (Impact Of Nicorandil in Angina)</p><p>trial (n = 5126), nicorandil significantly reduced the composite of cor-</p><p>onary heart disease (CHD) death, non-fatal MI, or unplanned hospital</p><p>admission for suspected anginal symptoms in patients with CCS, but</p><p>there was no effect on death from ischaemic heart disease or non-</p><p>ESC Guidelines 433</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..fatal MI.246 These results support the use of nicorandil as a second-</p><p>line drug in patients with CCS.</p><p>3.3.1.2.6 Ranolazine. Ranolazine is a selective inhibitor of the late</p><p>inward sodium current. Side effects include dizziness, nausea, and</p><p>constipation. In addition, ranolazine increases QTc, and should there-</p><p>fore be used carefully in patients with QT prolongation or on QT-</p><p>prolonging drugs.</p><p>In a placebo-controlled trial of 6560 patients with non-ST-segment</p><p>elevation ACS, the addition of ranolazine to standard treatment did</p><p>not prove effective in reducing the primary efficacy endpoint of cardi-</p><p>ovascular death, MI, or recurrent ischaemia.247</p><p>. . . . . . . 419</p><p>3.1.2 Step 2: comorbidities and other causes of symptoms . . . . . 419</p><p>3.1.3 Step 3: basic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419</p><p>3.1.3.1 Biochemical tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419</p><p>3.1.3.2 Resting electrocardiogram and ambulatory</p><p>monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420</p><p>3.1.3.3 Echocardiography and magnetic resonance</p><p>imaging at rest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420</p><p>3.1.3.4 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421</p><p>3.1.4 Step 4: assess pre-test probability and clinical likelihood</p><p>of coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421</p><p>3.1.5 Step 5: select appropriate testing . . . . . . . . . . . . . . . . . . . . . . . . 422</p><p>3.1.5.1 Functional non-invasive tests . . . . . . . . . . . . . . . . . . . . . . . 422</p><p>3.1.5.2 Anatomical non-invasive evaluation . . . . . . . . . . . . . . . . 423</p><p>3.1.5.3 Role of the exercise electrocardiogram . . . . . . . . . . . . . 423</p><p>3.1.5.4 Selection of diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . 424</p><p>3.1.5.5 The impact of clinical likelihood on the selection</p><p>of a diagnostic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424</p><p>3.1.5.6 Invasive testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425</p><p>3.1.6 Step 6: assess event risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427</p><p>3.1.6.1 Definition of levels of risk . . . . . . . . . . . . . . . . . . . . . . . . . . 428</p><p>3.2 Lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429</p><p>3.2.1 General management of patients with coronary artery</p><p>disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429</p><p>3.2.2 Lifestyle modification and control of risk factors . . . . . . . . . 429</p><p>3.2.2.1 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429</p><p>3.2.2.2 Diet and alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>3.2.2.3 Weight management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>3.2.2.4 Physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>3.2.2.5 Cardiac rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>3.2.2.6 Psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>3.2.2.7 Environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431</p><p>3.2.2.8 Sexual activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431</p><p>3.2.2.9 Adherence and sustainability . . . . . . . . . . . . . . . . . . . . . . . 431</p><p>3.2.2.10 Influenza vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431</p><p>3.3 Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432</p><p>3.3.1 Anti-ischaemic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432</p><p>3.3.1.1 General strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432</p><p>3.3.1.2 Available drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432</p><p>3.3.1.3 Patients with low blood pressure . . . . . . . . . . . . . . . . . . . 435</p><p>3.3.1.4 Patients with low heart rate . . . . . . . . . . . . . . . . . . . . . . . . 435</p><p>3.3.2 Event prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436</p><p>3.3.2.1 Antiplatelet drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436</p><p>3.3.2.2 Anticoagulant drugs in sinus rhythm . . . . . . . . . . . . . . . . 436</p><p>3.3.2.3 Anticoagulant drugs in atrial fibrillation . . . . . . . . . . . . . . 437</p><p>3.3.2.4 Proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437</p><p>3.3.2.5 Cardiac surgery and antithrombotic therapy . . . . . . . . 437</p><p>3.3.2.6 Non-cardiac surgery and antithrombotic therapy . . . 438</p><p>3.3.3 Statins and other lipid-lowering drugs . . . . . . . . . . . . . . . . . . . 440</p><p>3.3.4 Renin-angiotensin-aldosterone system blockers . . . . . . . . . 440</p><p>3.3.5 Hormone replacement therapy . . . . . . . . . . . . . . . . . . . . . . . . . 441</p><p>408 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>http://www.escardio.org/guidelines</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>3.4 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441</p><p>4. Patients with new onset of heart failure or reduced left</p><p>ventricular function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442</p><p>5. Patients with a long-standing diagnosis of chronic coronary</p><p>syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444</p><p>5.1 Patients with stabilized symptoms 1 year after initial diagnosis or revascularization . . . . 444</p><p>6. Angina without obstructive disease in the epicardial</p><p>coronary arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446</p><p>6.1 Microvascular angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447</p><p>6.1.1 Risk stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447</p><p>6.1.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447</p><p>6.1.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447</p><p>6.2 Vasospastic angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448</p><p>6.2.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448</p><p>6.2.2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448</p><p>7. Screening for coronary artery disease in asymptomatic subjects . . 449</p><p>8. Chronic coronary syndromes in specific circumstances . . . . . . . . . . 450</p><p>8.1 Cardiovascular comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>8.1.1 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>8.1.2 Valvular heart disease (including planned transcatheter</p><p>aortic valve implantation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>8.1.3 After heart transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>8.2 Non-cardiovascular comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . 451</p><p>8.2.1 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451</p><p>8.2.2 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451</p><p>8.2.3 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452</p><p>8.2.4 Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .</p><p>However, in the rela-</p><p>tively large subgroup of patients with chronic angina (n = 3565),</p><p>significant reductions in recurrent ischaemia, worsening angina, and</p><p>intensification of antianginal therapy were observed.248 In another</p><p>placebo-controlled trial of patients with diabetes and CAD receiving</p><p>one or two antianginal drugs, ranolazine reduced angina and sublin-</p><p>gual nitroglycerin use with good tolerability.249 In the RIVER-PCI</p><p>(Ranolazine for Incomplete Vessel Revascularization Post-</p><p>Percutaneous Coronary Intervention) trial, ranolazine did not reduce</p><p>the composite of ischaemia-driven revascularization or</p><p>hospitalization without revascularization in 2651 patients with a his-</p><p>tory of chronic angina and incomplete revascularization after PCI,</p><p>including those with and without PCI for a CAD indication, nor did it</p><p>reduce angina symptoms at 1 year.250,251</p><p>These results support the use of ranolazine as a second-line drug</p><p>in CCS patients with refractory angina despite commonly used anti-</p><p>anginal agents such as beta-blockers, CCBs, and/or long-acting</p><p>nitrates. Conversely, there is a lack of evidence to support the use of</p><p>ranolazine in patients with CCS following PCI with incomplete</p><p>revascularization.</p><p>3.3.1.2.7 Trimetazidine. Trimetazidine appears to have a haemodynami-</p><p>cally neutral side effect profile.252 Trimetazidine (35 mg b.i.d.) added to</p><p>beta-blockade (atenolol) improved effort-induced myocardial ischae-</p><p>mia, as reviewed by the European Medicines Agency in June</p><p>2012.253,254 It remains contraindicated in Parkinson’s disease and</p><p>motion disorders, such as tremor (shaking), muscle rigidity, walking dis-</p><p>orders, and restless leg syndrome. A 2014 meta-analysis of 13, mostly</p><p>Chinese, studies consisting of 1628 patients showed that treatment</p><p>with trimetazidine on top of other antianginal drugs was associated</p><p>with a smaller weekly mean number of angina attacks, lower weekly</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>BB orCCBa BB or</p><p>non-DHP-CCB DHP-CCB BB Low-dose BBor low-dose</p><p>non-DHP-CCBc1ststep</p><p>Standard</p><p>therapy</p><p>High heartrate (e.g.</p><p>>80 bpm)</p><p>Low heart rate (e.g.</p><p>2 years.257 However, the</p><p>role of allopurinol in reducing clinical events in CVD remains</p><p>unclear.258</p><p>A stepwise strategy for anti-ischaemic drug therapy in CCS is pro-</p><p>posed, depending on some baseline patient characteristics (Figure 8).</p><p>Incomplete responses or poor tolerance at each step justify moving</p><p>to the next step. The strategy must be adapted to each patient’s</p><p>characteristics and preferences, and does not necessarily follow the</p><p>steps indicated in the figure.</p><p>3.3.1.3 Patients with low blood pressure</p><p>In patients with low BP, it is recommended to start antianginal drugs at</p><p>very low doses, with preferential use of drugs with no or limited effects</p><p>on BP. A low-dose beta-blocker or low-dose non-DHP-CCB can be</p><p>tested first under close monitoring of tolerance. Ivabradine (in patients</p><p>with sinus rhythm), ranolazine, or trimetazidine can also be used.</p><p>3.3.1.4 Patients with low heart rate</p><p>Increased heart rate correlates linearly with cardiovascular</p><p>events, and the benefit of heart-rate reduction as a treatment</p><p>goal in subgroups of CCS patients has been demonstrated using</p><p>various drugs.203,259�261 However, in patients with baseline bra-</p><p>dycardia (e.g. heart rate</p><p>In subjects with baseline low heart rate and low BP, ranolazine or trimetazidine may be considered as a first-line drug to</p><p>reduce angina frequency and improve exercise tolerance.</p><p>IIb C</p><p>In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine,</p><p>and trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance.198 IIb B</p><p>Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy266 or co-administration of phos-</p><p>phodiesterase inhibitors.267 III B</p><p>BP = blood pressure; CCB = calcium channel blocker; CCS = chronic coronary syndromes; DHP-CCB = dihydropyridine calcium channel blocker.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>cNo demonstration of benefit on prognosis.</p><p>ESC Guidelines 435</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>3.3.2 Event prevention</p><p>3.3.2.1 Antiplatelet drugs</p><p>Platelet activation and aggregation is the driver for symptomatic cor-</p><p>onary thrombosis, forming the basis for the use of antiplatelet drugs</p><p>in patients with CCS in view of a favourable balance between the pre-</p><p>vention of ischaemic events and increased risk of bleeding. Dual anti-</p><p>platelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor is</p><p>the mainstay of antithrombotic therapy after MI and/or PCI.</p><p>3.3.2.1.1 Low-dose aspirin. Aspirin acts via irreversible inhibition of pla-</p><p>telet cyclooxygenase-1 and thus thromboxane production, which is</p><p>normally complete with chronic dosing >_75 mg/day. The gastrointes-</p><p>tinal side effects of aspirin increase at higher doses, and current evi-</p><p>dence supports a daily dose of 75�100 mg for the prevention of</p><p>ischaemic events in CAD patients with or without a history of</p><p>MI.268�270 As cyclooxygenase-1 inhibition by aspirin is consistent and</p><p>predictable in adherent patients, no platelet function testing is</p><p>required to monitor individual response.271 Although other non-</p><p>selective non-steroidal anti-inflammatory drugs, such as ibuprofen,</p><p>reversibly inhibit cyclooxygenase-1, their adverse effects on cardio-</p><p>vascular risk indicate that they cannot be recommended as an alter-</p><p>native treatment in patients with aspirin intolerance.272</p><p>3.3.2.1.2 Oral P2Y12 inhibitors. P2Y12 inhibitors block the platelet P2Y12</p><p>receptor, which plays a key role in platelet activation and the amplifi-</p><p>cation of arterial thrombus formation. Clopidogrel and prasugrel are</p><p>thienopyridine prodrugs that irreversibly block P2Y12 via active</p><p>metabolites. Ticagrelor is a reversibly-binding P2Y12 inhibitor that</p><p>does not require metabolic activation.</p><p>The CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of</p><p>Ischaemic Events) trial showed an overall slight benefit of clopidogrel</p><p>compared with aspirin, with a similar safety profile, in preventing car-</p><p>diovascular events in patients with previous MI, previous stroke, or</p><p>PAD.273 Subgroup analysis suggested greater benefit of clopidogrel in</p><p>patients with PAD. Despite its lesser antiplatelet efficacy, clopidogrel</p><p>demonstrated equivalent efficacy to ticagrelor in patients with</p><p>PAD.274 Clopidogrel is limited by variable pharmacodynamic effects</p><p>related to variable efficiency of conversion to its active metabolite,</p><p>partly associated with loss-of-function variants in the CYP2C19 gene,</p><p>leading to a lack of efficacy in some patients.271 Drugs that inhibit</p><p>CYP2C19, such as omeprazole, may reduce the response to</p><p>clopidogrel.275</p><p>Prasugrel has more rapid, more predictable, and, on average,</p><p>greater antiplatelet effect compared with clopidogrel, and is not sus-</p><p>ceptible to drug interactions or the effect of CYP2C19 loss-of-</p><p>function variants. Prasugrel has greater efficacy than clopidogrel in</p><p>aspirin-treated patients with ACS undergoing PCI, but not in medically-</p><p>managed patients with ACS.276,277 Prasugrel has been associated with</p><p>more non-fatal and fatal bleeding events than clopidogrel in ACS</p><p>patients undergoing PCI, leading to apparent harm in those with a his-</p><p>tory of ischaemic stroke, and a lack of apparent benefit in those aged</p><p>>75 years or with body weight _1 year after MI,</p><p>reduced ischaemic events at the expense of more non-fatal bleed-</p><p>ing.284 The 60 mg dose appeared better tolerated and is approved in</p><p>many countries for this indication. Subgroup analysis demonstrated</p><p>greater absolute reductions in ischaemic events with long-term tica-</p><p>grelor (60 mg b.i.d.) in higher-risk post-MI patients with diabetes,</p><p>PAD, or multivessel CAD.291�293</p><p>3.3.2.2 Anticoagulant drugs in sinus rhythm</p><p>Anticoagulant drugs inhibit the action and/or formation of thrombin,</p><p>which plays a pivotal role in both coagulation and platelet activation.</p><p>Consequently, anticoagulants have been shown to reduce the risk of</p><p>arterial thrombotic events. The superior efficacy and safety of DAPT,</p><p>436 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>compared with aspirin and anticoagulation, in preventing stent</p><p>thrombosis led to the latter strategy being abandoned in favour of</p><p>DAPT following PCI.284 Combination of antiplatelet therapy and</p><p>standard anticoagulant doses of warfarin or apixaban for secondary</p><p>prevention after ACS was associated with an unfavourable balance of</p><p>efficacy and bleeding.294,295 However, recently reported studies have</p><p>renewed interest in combining lower anticoagulant doses with anti-</p><p>platelet therapy.</p><p>3.3.2.2.1 Low-dose rivaroxaban. Rivaroxaban is a factor Xa inhibitor</p><p>that has been studied at a low dose of 2.5 mg b.i.d. in several popula-</p><p>tions of patients in sinus rhythm, this dose being one-quarter of the</p><p>standard dose used for anticoagulation in patients with AF.</p><p>Rivaroxaban 2.5 mg b.i.d., compared with placebo, reduced the com-</p><p>posite of MI, stroke, or cardiovascular death in stabilized patients</p><p>treated predominantly with aspirin and clopidogrel following ACS, at</p><p>the expense of increased bleeding but with evidence of a reduction in</p><p>cardiovascular death.296 Subsequently, in the COMPASS</p><p>(Cardiovascular Outcomes for People Using Anticoagulation</p><p>Strategies) trial, the same regimen in combination with aspirin was</p><p>compared with aspirin alone, as well as rivaroxaban 5 mg b.i.d. alone,</p><p>in patients with CCS or PAD, and showed reduced ischaemic events</p><p>at the expense of increased risk of predominantly non-fatal bleed-</p><p>ing.297 Of note, the pre-specified significance thresholds for cardio-</p><p>vascular mortality and all-cause mortality were not met. Greater</p><p>absolute risk reductions were seen in higher-risk patients with diabe-</p><p>tes, PAD, or moderate chronic kidney disease (CKD), as well as cur-</p><p>rent smokers. In GEMINI-ACS (A Study to Compare the Safety of</p><p>Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either</p><p>Clopidogrel or Ticagrelor Therapy in Participants With Acute</p><p>Coronary Syndrome), rivaroxaban 2.5 mg b.i.d. was compared with</p><p>aspirin in patients treated with a P2Y12 inhibitor who were stable fol-</p><p>lowing PCI. The results suggested similar safety of rivaroxaban to</p><p>aspirin in this setting, but larger studies are required to substantiate</p><p>this finding.298 In addition, the safety of performing PCI without</p><p>aspirin pre-treatment is unknown.</p><p>3.3.2.3 Anticoagulant drugs in atrial fibrillation</p><p>Anticoagulant therapy is recommended in patients with AF and CCS</p><p>for reduction of ischaemic stroke and other ischaemic events.</p><p>Anticoagulants in AF patients have demonstrated superiority over</p><p>aspirin monotherapy or clopidogrel-based DAPT for stroke preven-</p><p>tion, and are therefore recommended for this indication.299 When</p><p>oral anticoagulation is initiated in a patient with AF who is eligible for</p><p>a non-vitamin K antagonist oral anticoagulant (NOAC; apixaban,</p><p>dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in</p><p>preference to a vitamin K antagonist (VKA).299</p><p>3.3.2.3.1 Combination anticoagulant and antiplatelet therapy following per-</p><p>cutaneous coronary intervention for patients with atrial fibrillation or</p><p>another indication for oral anticoagulation. No studies to date have spe-</p><p>cifically focused on CCS patients with AF undergoing PCI and clinical</p><p>decisions must be based on clinical trials that have included a large</p><p>proportion of patients with ACS. For peri-procedural management,</p><p>it is recommended that interruption of VKA is avoided, if feasible,</p><p>whereas it is recommended that NOAC therapy is stopped for</p><p>12�48 h before elective PCI, depending on renal function and the</p><p>particular NOAC regimen.300 Radial artery access is preferred along</p><p>with intraprocedural unfractionated heparin either at a standard dose</p><p>(70�100 U/kg) or, in those with uninterrupted VKA, at a lower dose</p><p>of 30�50 U/kg.300 Pre-treatment with aspirin 75�100 mg daily is rec-</p><p>ommended, and clopidogrel (300�600 mg loading dose if not on</p><p>long-term maintenance therapy) is recommended in preference to</p><p>prasugrel or ticagrelor.300 VKA-treated patients receiving aspirin and</p><p>clopidogrel post-PCI should have a target international normalized</p><p>ratio in the range of 2.0�2.5, aiming for high time in therapeutic range</p><p>(>70%).300 Subsequent to post-PCI trials of different antithrombotic</p><p>regimens considered in previous Guidelines,88,284 the AUGUSTUS</p><p>trial (An Open-label, 2� 2 Factorial, Randomized Controlled,</p><p>Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K</p><p>Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial</p><p>Fibrillation and Acute Coronary Syndrome or Percutaneous</p><p>Coronary Intervention) showed, firstly, that apixaban 5 mg b.i.d. (i.e.</p><p>the licensed dose for thromboprophylaxis in AF) was associated with</p><p>significantly less major or clinically relevant non-major bleeding than</p><p>VKA; and, secondly, that aspirin, compared with placebo, was associ-</p><p>ated with significantly more bleeding, with the safest combination</p><p>being apixaban and placebo in addition to P2Y12 inhibitor (predomi-</p><p>nantly clopidogrel).301 However, there were numerically, but not</p><p>statistically significantly, more stent thrombosis events with placebo</p><p>than with aspirin, and the trial was not powered to assess differences</p><p>in these events between groups.301 Consequently, when concerns</p><p>about thrombotic risk prevail over concerns about bleeding risk, >_1</p><p>month of triple therapy [oral anticoagulant (OAC), aspirin, and clopi-</p><p>dogrel] is recommended to cover the period when the risk of stent</p><p>thrombosis is presumed to exceed the risk of bleeding.300,301 There</p><p>is currently limited evidence to support the use of OACs with tica-</p><p>grelor or prasugrel as dual therapy after PCI as an alternative to triple</p><p>therapy.300,301</p><p>3.3.2.3.2 Long-term combination therapy in patients with atrial fibrillation</p><p>or another indication for anticoagulation. OAC monotherapy is gener-</p><p>ally recommended 6�12 months after PCI in patients with AF, as</p><p>there is a lack of specific data supporting long-term treatment with an</p><p>OAC and a single antiplatelet agent; however, in highly selected cases</p><p>with high ischaemic risk, dual therapy with an OAC and aspirin or clo-</p><p>pidogrel may be considered.300</p><p>3.3.2.4 Proton pump inhibitors</p><p>Proton pump inhibitors reduce the risk of gastrointestinal bleeding in</p><p>patients treated with antiplatelet drugs and may be a useful adjunctive</p><p>treatment for improving safety.275 Long-term proton pump inhibitor</p><p>use is associated with hypomagnesaemia, but the role of monitoring</p><p>serum magnesium levels is uncertain. Proton pump inhibitors that</p><p>inhibit CYP2C19, particularly omeprazole and esomeprazole, may</p><p>reduce the pharmacodynamic response to clopidogrel. Although this</p><p>has not been shown to affect the risk of ischaemic events or stent</p><p>thrombosis, co-administration of omeprazole or esomeprazole with</p><p>clopidogrel is generally not recommended.</p><p>3.3.2.5 Cardiac surgery and antithrombotic therapy</p><p>Aspirin should normally be continued in patients with CCS under-</p><p>going elective cardiac surgery, and other antithrombotic drugs</p><p>stopped at intervals according to their duration of action and</p><p>ESC Guidelines 437</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>indication (prasugrel stopped >_7 days before; clopidogrel >_5 days</p><p>before; ticagrelor >_3 days before; and rivaroxaban, apixaban, edoxa-</p><p>ban, and dabigatran 1�2 days before depending on dose and renal</p><p>function). Reloading of aspirin after CABG surgery may improve graft</p><p>patency.302 The role of DAPT or dual therapy with aspirin and rivar-</p><p>oxaban after CABG surgery is uncertain as large prospective studies</p><p>are lacking. However, RCT results have suggested higher graft</p><p>patency rates with DAPT compared with aspirin</p><p>monotherapy.284,303,304</p><p>3.3.2.6 Non-cardiac surgery and antithrombotic therapy</p><p>Non-cardiac surgery is associated with an increased risk of MI.</p><p>Following PCI, whenever possible, it is recommended to postpone</p><p>elective surgery until the recommended course of DAPT has been</p><p>completed. Usually, this will mean delaying surgery until 6 months</p><p>after PCI, but surgery between 3�6 months may be considered by</p><p>a multidisciplinary team, including an interventional cardiologist, if</p><p>clinically indicated. In most types of surgery, aspirin should be con-</p><p>tinued as the benefit outweighs the bleeding risk, but this may not</p><p>be appropriate for procedures associated with extremely high</p><p>bleeding risk (intracranial procedures, transurethral prostatectomy,</p><p>intraocular procedures, etc.).284 The COMPASS study included</p><p>CCS patients with a history of peripheral revascularization proce-</p><p>dures, and demonstrated benefits of aspirin and rivaroxaban 2.5 mg</p><p>b.i.d. compared with aspirin alone, including reductions in major</p><p>adverse limb events and mortality, suggesting the need to risk-</p><p>stratify patients after non-cardiac vascular surgery for atheroscler-</p><p>otic disease.305,306</p><p>Recommendations for event prevention I</p><p>Recommendations Classa Levelb</p><p>Antithrombotic therapy in patients with CCS and in sinus rhythm</p><p>Aspirin 75�100 mg daily is recommended in patients with a previous MI or revascularization.270 I A</p><p>Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance.273 I B</p><p>Clopidogrel 75 mg daily may be considered in preference to aspirin in symptomatic or asymptomatic patients, with either</p><p>PAD or a history of ischaemic stroke or transient ischaemic attack.273 IIb B</p><p>Aspirin 75�100 mg daily may be considered in patients without a history of MI or revascularization, but with definitive evi-</p><p>dence of CAD on imaging.</p><p>IIb C</p><p>Adding a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with</p><p>a high risk of ischaemic eventsc and without high bleeding riskd (see Table 9 for options).289,296,297,307 IIa A</p><p>Adding a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at</p><p>least a moderately increased risk of ischaemic eventse and without high bleeding riskd (see Table 9 for</p><p>options).289,296,297,307</p><p>IIb A</p><p>Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm</p><p>Aspirin 75�100 mg daily is recommended following stenting.284 I A</p><p>Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) is recommended,</p><p>in addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (1�3</p><p>months) is indicated due to risk or the occurrence of life-threatening bleeding.284</p><p>I A</p><p>Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) should be consid-</p><p>ered for 3 months in patients with a higher risk of life-threatening bleeding.284 IIa A</p><p>Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) may be considered</p><p>for 1 month in patients with very high risk of life-threatening bleeding.284 IIb C</p><p>Prasugrel or ticagrelor may be considered, at least as initial therapy, in specific high-risk situations of elective stenting (e.g.</p><p>suboptimal stent deployment or other procedural characteristics associated with high risk of stent thrombosis, complex</p><p>left main stem, or multivessel stenting) or if DAPT cannot be used because of aspirin intolerance.</p><p>IIb C</p><p>Antithrombotic therapy in patients with CCS and AF</p><p>When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC,f a NOAC is recommended in pref-</p><p>erence to a VKA.299�301,308�311 I A</p><p>Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and</p><p>a CHA2DS2-VASc scoreg >_2 in males and >_3 in females.299 I A</p><p>Continued</p><p>438 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF</p><p>and a CHA2DS2-VASc scoreg of 1 in males and 2 in females.299 IIa B</p><p>Aspirin 75�100 mg daily (or clopidogrel 75 mg daily) may be considered in addition to long-term OAC therapy in patients</p><p>with AF, history of MI, and at high risk of recurrent ischaemic eventsc who do not have a high bleeding risk.d 295,297,299 IIb B</p><p>Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC</p><p>It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent</p><p>implantation.</p><p>I C</p><p>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.,</p><p>edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.)f is used in preference to a VKA in combination with antiplatelet</p><p>therapy.300,301,308,310,311</p><p>I A</p><p>When rivaroxaban is used and concerns about high bleeding riskd prevail over concerns about stent thrombosish or</p><p>ischaemic stroke,g rivaroxaban 15 mg o.d. should be considered in preference to rivaroxaban 20 mg o.d. for the duration</p><p>of concomitant single or dual antiplatelet therapy.300,301,308,310</p><p>IIa B</p><p>When dabigatran is used and concerns about high bleeding riskd prevail over concerns about stent thrombosish or ischae-</p><p>mic stroke,g dabigatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for the duration of</p><p>concomitant single or dual antiplatelet therapy.300,301,308</p><p>IIa B</p><p>After uncomplicated PCI, early cessation (_1 month should be considered when the risk of stent throm-</p><p>bosish outweighs the bleeding risk, with the total duration (70%.300,301,308�310</p><p>IIa B</p><p>Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with</p><p>an OAC, aspirin, and clopidogrel in patients with a moderate or high risk of stent thrombosis,h irrespective of the type of</p><p>stent used.</p><p>IIb C</p><p>The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C</p><p>Use of proton pump inhibitors</p><p>Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC</p><p>monotherapy who are at high risk of gastrointestinal bleeding.284 I A</p><p>AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA2DS2-VASc = Cardiac failure, Hypertension,</p><p>Age >_75 [Doubled], Diabetes, Stroke [Doubled] � Vascular disease, Age 65�74 and Sex</p><p>category [Female]; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy;</p><p>eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant;</p><p>o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>cDiffuse 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 m2.</p><p>dPrior history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointes-</p><p>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-</p><p>ure requiring dialysis or with eGFR 75�80 years, and/or drug</p><p>interactions.</p><p>gCongestive HF, hypertension, age >_75 years (2 points), diabetes, prior stroke/transient ischaemic attack/embolus (2 points), vascular disease (CAD on imaging or angiogra-</p><p>phy,312 prior MI, PAD, or aortic plaque), age 65�74 years, and female sex.</p><p>hRisk 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-</p><p>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;</p><p>stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antith-</p><p>rombotic therapy.</p><p>ESC Guidelines 439</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>3.3.3 Statins and other lipid-lowering drugs</p><p>Dyslipidaemia should be managed according to lipid guidelines with</p><p>pharmacological and lifestyle intervention.315 Patients with estab-</p><p>lished CAD are regarded as being at very high risk for cardiovascular</p><p>events and statin treatment must be considered, irrespective of LDL-</p><p>C levels. The goal of treatment is to lower LDL-C by at least 50%</p><p>from baseline and to _5.0 mmol/L.340</p><p>Table 9 Treatment options for dual antithrombotic therapy in combination with aspirin 75 2 100 mg daily in patients</p><p>who have a higha or moderateb risk of ischaemic events, and do not have a high bleeding riskc</p><p>Drug option Dose Indication Additional cautions References</p><p>Clopidogrel 75 mg o.d. Post-MI in patients who have tolerated DAPT for 1 year 289,290</p><p>Prasugrel 10 mg o.d or 5 mg o.d.; if body</p><p>weight 75 years</p><p>Post-PCI for MI in patients who have tolerated</p><p>DAPT for 1 year</p><p>Age >75 years 289,290,313</p><p>Rivaroxaban 2.5 mg b.i.d. Post-MI >1 year or multivessel CAD Creatinine clearance</p><p>15 - 29 mL/min</p><p>297</p><p>Ticagrelor 60 mg b.i.d. Post-MI in patients who have tolerated DAPT for 1 year 291�293,307,314</p><p>Treatment options are presented in alphabetical order.</p><p>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;</p><p>HF = heart failure;</p><p>MI = myocardial infarction; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention.</p><p>aHigh 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</p><p>eGFR 15 - 59 mL/min/1.73 m2.</p><p>bModerately increased risk of ischaemic events is defined as at least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD,</p><p>HF, or CKD with eGFR 15 - 59 mL/min/1.73 m2.</p><p>cHigh bleeding risk is defined as history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia</p><p>due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old</p><p>age or frailty, or renal failure requiring dialysis or with eGFR 60 years.344</p><p>3.4 Revascularization</p><p>In patients with CCS, optimal medical therapy is key for reducing</p><p>symptoms, halting the progression of atherosclerosis, and preventing</p><p>atherothrombotic events. Myocardial revascularization plays a cen-</p><p>tral role in the management of CCS on top of medical treatment, but</p><p>always as an adjunct to medical therapy without supplanting it. The</p><p>two objectives of revascularization are symptom relief in patients</p><p>with angina and/or improvement of prognosis.</p><p>Previous Guidelines support indications for revascularization</p><p>mainly in patients with CCS who receive Guideline-recommended</p><p>optimal medical therapy and continue to be symptomatic, and/or in</p><p>whom revascularization may ameliorate prognosis.88 These recom-</p><p>mendations suggested that revascularization in patients with angina</p><p>and significant stenosis was often a second-line therapy after medical</p><p>therapy had been unsuccessful. However, angina is associated with</p><p>impaired quality of life, reduced physical endurance, mental depres-</p><p>sion, and recurrent hospitalizations and office visits, with impaired</p><p>clinical outcomes.345,346</p><p>Revascularization by PCI or CABG may effectively relieve angina,</p><p>reduce the use of antianginal drugs, and improve exercise capacity</p><p>and quality of life compared with a strategy of medical therapy</p><p>alone. In the 5 year follow-up of the FAME 2 (Fractional Flow</p><p>Reserve versus Angiography for Multivessel Evaluation 2) trial, revas-</p><p>cularization improved quality of life, and reduced the use of antiangi-</p><p>nal drugs and associated side effects.347 The ORBITA (Objective</p><p>Randomised Blinded Investigation with optimal medical Therapy or</p><p>Angioplasty in stable angina) study, entailing a sham procedure in the</p><p>control group, found no significant improvement in exercise capacity</p><p>with PCI.262 The study highlights a significant placebo component to</p><p>the clinical effects, and alerts us to the pitfalls of interpreting end-</p><p>points subject to bias in the absence of sham control and blinding.</p><p>However, the ORBITA results cannot inform Guidelines due to the</p><p>limited trial size, short-term observation time until crossover, and</p><p>insufficient power to assess clinical endpoints.</p><p>Revascularization by either PCI or CABG also aims to effectively</p><p>eliminate myocardial ischaemia and its adverse clinical manifestations</p><p>among patients with significant coronary stenosis, and to reduce the</p><p>risk of major acute cardiovascular events including MI and cardiovas-</p><p>cular death. Numerous meta-analyses comparing a strategy of PCI</p><p>with initial medical therapy among patients with CCS have found</p><p>no348,349 or a modest104,350,351 benefit, in terms of survival or MI for</p><p>an invasive strategy. In this regard, previous Guidelines identified spe-</p><p>cific subgroups of patients (based on the anatomy of the coronary</p><p>tree, LV function, risk factors, etc.) in whom revascularization may</p><p>improve prognosis, indicating that in other groups it may not.88</p><p>A meta-analysis by Windecker et al. reported an incremental</p><p>reduction of death and MI by revascularization vs. medical therapy</p><p>only in CCS patients when revascularization was performed with</p><p>CABG or new-generation drug-eluting stents (DES), as opposed to</p><p>balloon angioplasty, bare-metal stents, or early DES.351 Data</p><p>reported in 2018 indicate a potentially broader prognostic impact of</p><p>revascularization strategies. The 5 year follow-up of the FAME 2 trial</p><p>confirmed a sustained clinical benefit in patients treated with PCI spe-</p><p>cifically targeting the ischaemia-producing stenoses (i.e. FFR 10%), when PCI is</p><p>restricted to angiographic stenoses on large vessels causing a signifi-</p><p>cant intracoronary pressure gradient. Figure 9 summarizes a practical</p><p>approach to the indications of revascularization in CCS according to</p><p>the presence or absence of symptoms, and documentation of non-</p><p>invasive ischaemia. However, the individual risk-benefit ratio should</p><p>always be evaluated and revascularization considered only if its</p><p>expected benefit outweighs its potential risk. Also, the aspect of</p><p>shared decision-making is key, with full information given to the</p><p>patient</p><p>about the anticipated advantages and disadvantages of the</p><p>two strategies, including the DAPT-related bleeding risks in cases of</p><p>revascularization by PCI. For the discussion of the best choice</p><p>between revascularization modalities�PCI or CABG�for individual</p><p>patients, we refer readers to the 2018 ESC myocardial revasculariza-</p><p>tion Guidelines.88</p><p>4 Patients with new onset of heart</p><p>failure or reduced left ventricular</p><p>function</p><p>CAD is the most common cause of HF in Europe, and most of the</p><p>trial evidence supporting management recommendations is based on</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>NoYes</p><p>NoYesNoYes</p><p>NoYes</p><p>Diameter stenosis</p><p>>90%</p><p>FFR ≤0.80 or iwFR</p><p>≤0.89 in major</p><p>vessel</p><p>LVEF ≤35% due</p><p>to CAD</p><p>Large area</p><p>of ischaemia</p><p>(>10% of LV)</p><p>Diameter stenosis</p><p>>90%</p><p>FFR ≤0.80 or iwFR</p><p>≤0.89 in major</p><p>vessel</p><p>LVEF ≤35% due</p><p>to CAD</p><p>Identify lesions with</p><p>FFR ≤0.80 or</p><p>iwFR ≤0.89</p><p>•</p><p>•</p><p>•</p><p>•</p><p>•</p><p>•</p><p>Consider revascularization on top of medical therapy</p><p>MVD</p><p>Documented</p><p>ischaemia</p><p>Documented</p><p>ischaemia</p><p>Angina symptoms</p><p>Figure 9 Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention</p><p>or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or</p><p>absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prog-</p><p>nostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD</p><p>= coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricle; LVEF = left ventricular ejection fraction;</p><p>MVD = multivessel disease.</p><p>442 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..research conducted in patients with ischaemic cardiomyopathy. The</p><p>pathophysiology results in systolic dysfunction due to myocardial</p><p>injury and ischaemia, and most patients with symptomatic HF have</p><p>reduced ejection fraction (_50%). Patients with symptomatic HF should be managed clinically</p><p>according to the 2016 ESC heart failure Guidelines.340</p><p>History should include the assessment of symptoms suggestive of</p><p>HF, especially exercise intolerance and dyspnoea on exertion. All</p><p>major past events related to CAD including MI and revascularization</p><p>procedures are recorded, as well as all major cardiovascular comor-</p><p>bidity requiring treatment such as AF, hypertension, or valvular dys-</p><p>function, and non-cardiovascular comorbidity such as CKD, diabetes,</p><p>anaemia, or cancer. Current medical therapy, adherence, and toler-</p><p>ance should be reviewed.</p><p>Physical examination should assess the nutritional status of patients,</p><p>and estimate biological age and cognitive ability. Recorded physical</p><p>signs include heart rate, heart rhythm, supine BP, murmurs suggestive</p><p>of aortic stenosis or mitral insufficiency, signs of pulmonary conges-</p><p>tion with basal rales or pleural effusion, signs of systemic congestion</p><p>with dependant oedema, hepatomegaly, and elevated jugular venous</p><p>pressure.</p><p>A routine ECG provides information on heart rate and rhythm,</p><p>extrasystole, signs of ischaemia, pathological Q waves, hypertrophy,</p><p>conduction abnormalities, and bundle branch block.</p><p>Imaging should include an echocardiographic examination with</p><p>Doppler to evaluate evidence of ischaemic cardiomyopathy with HF</p><p>with reduced ejection fraction, HF with mid-range ejection fraction,</p><p>or HF with preserved ejection fraction, focal/diffuse LV or right ven-</p><p>tricular systolic dysfunction, evidence of diastolic dysfunction, hyper-</p><p>trophy, chamber volumes, valvular function, and evidence of</p><p>pulmonary hypertension. Chest X-ray can detect signs of pulmonary</p><p>congestion, interstitial oedema, infiltration, or pleural effusion. If not</p><p>known, coronary angiography (or coronary CTA) should be</p><p>performed to establish the presence and extent of CAD, and evalu-</p><p>ate the potential for revascularization.52,53</p><p>Laboratory investigations should measure natriuretic peptide levels to</p><p>rule-out the diagnosis of suspected HF. When present, the severity of</p><p>HF can be assessed.25,49 Renal function along with serum electrolytes</p><p>should be measured routinely to detect the development of renal</p><p>insufficiency, hyponatraemia, or hyperkalaemia, especially at the initia-</p><p>tion and during up-titration of pharmacological therapy.</p><p>The management of patients with symptomatic HF requires</p><p>adequate diuretic therapy, preferably with a loop diuretic, to relieve</p><p>signs and symptoms of pulmonary and systemic congestion.</p><p>Inhibitors of both the RAS system (ACE inhibitors, ARBs, angiotensin</p><p>receptor-neprilysin inhibitor) and the adrenergic nervous system</p><p>(beta-blockers) are indicated in all symptomatic patients with HF.340</p><p>In patients with persistent symptoms, an MRA is also indicated. Up-</p><p>titration of these drugs should be gradual to avoid symptomatic sys-</p><p>tolic hypotension, renal insufficiency, or hyperkalaemia.</p><p>Patients who remain symptomatic, with LV systolic dysfunction</p><p>and evidence of ventricular dysrhythmia or bundle branch block, may</p><p>be eligible for a device [cardiac resynchronization therapy (CRT)/</p><p>implantable cardioverter-defibrillator]. Such devices may provide</p><p>symptomatic relief, reduce morbidity, and improve survival.353�356</p><p>Patients with HF may decompensate rapidly following the onset of</p><p>atrial or ventricular dysrhythmia, and should be treated according to</p><p>current Guidelines. Patients with HF, and haemodynamically signifi-</p><p>cant aortic stenosis or mitral insufficiency, may require percutaneous</p><p>or surgical intervention.</p><p>Myocardial revascularization should be considered in eligible</p><p>patients with HF based on their symptoms, coronary anatomy, and</p><p>risk profile. Successful revascularization in patients with HF due to</p><p>ischaemic cardiomyopathy may improve LV dysfunction and progno-</p><p>sis by reducing ischaemia to viable, hibernating myocardium. If avail-</p><p>able, cooperation with a multidisciplinary HF team is strongly</p><p>advised.348,357,358</p><p>General recommendations for the management of patients with chronic coronary syndromes and symptomatic heart</p><p>failure due to ischaemic cardiomyopathy and left ventricular systolic dysfunction</p><p>Recommendations for drug therapy Classa Levelb</p><p>Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF</p><p>symptoms.359,360 I B</p><p>Beta-blockers are recommended as essential components of treatment due to their efficacy in both relieving angina, and</p><p>reducing morbidity and mortality in HF.214,361�367 I A</p><p>ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to</p><p>improve symptoms and reduce morbidity and mortality.333,368 I A</p><p>An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition, or an angiotensin recep-</p><p>tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.337,369 I B</p><p>An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and</p><p>beta-blocker, to reduce morbidity and mortality.360,370 I A</p><p>A short-acting oral or transcutaneous nitrate should be considered (effective antianginal treatment, safe in HF).371 IIa A</p><p>Ivabradine should be considered in patients with sinus rhythm, an LVEF 70 b.p.m. who</p><p>remain symptomatic despite adequate treatment with a beta-blocker, ACE inhibitor, and MRA, to reduce morbidity and</p><p>mortality.238,372,373</p><p>IIa B</p><p>Amlodipine may be considered for relief of angina in patients with HF who do not</p><p>tolerate beta-blockers, and is consid-</p><p>ered safe in HF.374,375 IIb B</p><p>Continued</p><p>ESC Guidelines 443</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>5 Patients with a long-standing</p><p>diagnosis of chronic coronary</p><p>syndromes</p><p>In patients with a long-standing diagnosis of CCS, lifelong treatment</p><p>and surveillance are required (Figure 10). The clinical course of</p><p>patients with CCS may be benign over the course of time. However,</p><p>patients with CCS may develop a variety of cardiovascular complica-</p><p>tions or undergo therapeutic measures, some directly related to the</p><p>underlying CAD, and some having therapeutic or prognostic interac-</p><p>tions with the underlying disease. Risk for complications may occur in</p><p>an otherwise asymptomatic patient, and thus the assessment of risk</p><p>status applies to symptomatic and asymptomatic patients.</p><p>Periodic assessment of the patient’s individual risk may be consid-</p><p>ered (Figure 10). Scores that apply clinical parameters have been</p><p>shown to predict outcomes among patients with CCS. Moreover, if</p><p>the clinical parameters are complemented by biomarkers, such a risk</p><p>score may be even more accurate. In 2017, a biomarker-based risk</p><p>model to predict cardiovascular mortality in patients with CCS was</p><p>developed and externally validated.398</p><p>5.1 Patients with stabilized symptoms 1 year after initial diagnosis</p><p>or revascularization</p><p>To assess a patient’s risk, an annual evaluation by a cardiovascular</p><p>practitioner (cardiologist, general physician, or nurse) is warranted,</p><p>even if the patient is asymptomatic. It is recommended that the</p><p>annual evaluation should assess the patient’s overall clinical status and</p><p>medication compliance, as well as the risk profile (as reflected by risk</p><p>scores). Laboratory tests—which include a lipid profile, renal func-</p><p>tion, a complete blood count, and possibly biomarkers—should be</p><p>performed every 2 years.45 A patient with a worsening risk score</p><p>over time may warrant more intense therapy or diagnostic measures,</p><p>although risk score-guided therapy has not yet been proved to ameli-</p><p>orate outcomes.</p><p>A 12 lead ECG should be a part of every such visit to delineate</p><p>heart rate and heart rhythm, to detect changes suggestive of silent</p><p>ischaemia/infarction, and to discern abnormalities in the specific elec-</p><p>trocardiographic segments (e.g. PR, QRS, and QT intervals). It may</p><p>be beneficial to assess LV function (diastolic and systolic), valvular sta-</p><p>tus, and cardiac dimensions in apparently asymptomatic patients</p><p>every 3�5 years.52,53 In cases of unexplained reduction in systolic LV</p><p>function, especially if regional, imaging of coronary artery anatomy is</p><p>recommended. Likewise, it may be beneficial to assess non-invasively</p><p>for silent ischaemia in an apparently asymptomatic patient every 3�5</p><p>For devices, comorbidities, and revascularization</p><p>In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker</p><p>rather than right ventricular pacing is recommended.353 I A</p><p>An implantable cardioverter-defibrillator is recommended in patients with documented ventricular dysrhythmia causing</p><p>haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF _150 ms and LBBB QRS</p><p>morphology, and with LVEF</p><p>set as a reference and/or</p><p>periodically (e.g. at 1 year if previously abnormal and/or every 3-5 years) to</p><p>evaluate LV function, valvular status and haemodynamic status.</p><p>D</p><p>es</p><p>ta</p><p>bi</p><p>liz</p><p>at</p><p>io</p><p>n</p><p>D</p><p>es</p><p>ta</p><p>bi</p><p>liz</p><p>at</p><p>io</p><p>n</p><p>St</p><p>ab</p><p>ili</p><p>za</p><p>tio</p><p>n</p><p>Baseline</p><p>3 months</p><p>6 months</p><p>12 months</p><p>T</p><p>im</p><p>e</p><p>fr</p><p>om</p><p>in</p><p>iti</p><p>al</p><p>e</p><p>va</p><p>lu</p><p>at</p><p>io</p><p>n</p><p>of</p><p>p</p><p>os</p><p>t-</p><p>A</p><p>C</p><p>S</p><p>C</p><p>C</p><p>S</p><p>18 months</p><p>24 months</p><p>Yearly</p><p>Post-ACS CCS</p><p>(e.g. >1 year after MI)</p><p>Yearly</p><p>Long-standing diagnosis</p><p>of CCS (>1 year)</p><p>Baseline</p><p>3 months</p><p>6 months</p><p>12 months</p><p>T</p><p>im</p><p>e</p><p>fr</p><p>om</p><p>in</p><p>iti</p><p>al</p><p>e</p><p>va</p><p>lu</p><p>at</p><p>io</p><p>n</p><p>of</p><p>r</p><p>ec</p><p>en</p><p>t</p><p>C</p><p>C</p><p>S</p><p>Recent CCS diagnosis</p><p>or revascularization</p><p>Legend Time for decision-making on</p><p>DAPT continuation in PCI patients</p><p>Time for decision-making on</p><p>optional dual antithrombotic therapy</p><p>(see table 9)</p><p>Advisable timepoint</p><p>Optional timepoint</p><p>Cardiovascular</p><p>caregivera visit</p><p>Risk score(s)</p><p>stratification</p><p>Resting</p><p>ECG</p><p>ACS</p><p>�</p><p>�</p><p>�</p><p>Figure 10 Proposed algorithm according to patient types commonly observed at chronic coronary syndrome outpatient clinics. The frequency of fol-</p><p>low-up may be subject to variation based on clinical judgement. ACS = acute coronary syndromes; CCS = chronic coronary syndromes; DAPT = dual anti-</p><p>platelet therapy; ECG = electrocardiogram; LV = left ventricular; MI = myocardial infarction; PCI = percutaneous coronary intervention. aCardiologist,</p><p>internist, general practitioner, or cardiovascular nurse.</p><p>ESC Guidelines 445</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..readily available biomarkers shown to predict prognosis in patients</p><p>with CCS include heart rate, haemoglobin, and white cell count.400</p><p>Scores based on aggregated biomarkers may have greater success</p><p>than individual biomarkers. A multiple biomarker score combining</p><p>high-sensitivity C-reactive protein, heat shock protein 70, and fibrin</p><p>degradation products significantly improved C-statistics and the net</p><p>reclassification index compared with a basic model using clinical</p><p>data.401 Similar results were reported for a combination of high-</p><p>sensitivity cardiac troponin T, NT-proBNP, and LDL-C.398 In several</p><p>studies, genetic risk scores have been shown to improve risk predic-</p><p>tion above traditional risk factors in general population samples402,403</p><p>and to predict recurrent events in populations with known</p><p>CCS.404�407 Although there is additional prognostic value in using</p><p>several individual and aggregated biomarkers, there is currently no</p><p>evidence that routine use leads to improved care. Nevertheless,</p><p>these measurements may have a role in selected patients (e.g. when</p><p>testing for haemostatic abnormalities in those with previous MI with-</p><p>out conventional risk factors or a strong family history of CAD).</p><p>Patients with unequivocal symptoms suggestive of ACS should be</p><p>expeditiously referred for evaluation, applying current Guidelines for</p><p>diagnosis and management. Among patients with more equivocal</p><p>symptoms, stress imaging is recommended408 and, if not available and</p><p>the ECG is amenable to identification of ischaemia, exercise stress</p><p>electrocardiography can be used as an alternative. In patients with</p><p>severe angina and a high-risk clinical profile, direct referral for ICA is</p><p>recommended, provided that ad hoc physiological assessment of hae-</p><p>modynamic stenosis significance is readily available in the catheteriza-</p><p>tion laboratory [e.g. instantaneous wave-free ratio (iwFR) or FFR].</p><p>Likewise, ICA is recommended for patients with evidence of signifi-</p><p>cant ischaemia obtained by non-invasive testing.</p><p>6 Angina without obstructive</p><p>disease in the epicardial coronary</p><p>arteries</p><p>In clinical practice, a marked discrepancy between findings regarding</p><p>coronary anatomy, the presence of symptoms, and the results of</p><p>non-invasive tests frequently occurs.13 These patients deserve atten-</p><p>tion, as angina and non-obstructive disease are associated with an</p><p>increased risk of adverse clinical events.14 Low diagnostic yield of ICA</p><p>can be explained by the presence of: (i) stenoses with mild or moder-</p><p>ate angiographic severity, or diffuse coronary narrowing, with under-</p><p>estimated functional significance identified by ICA; (ii) disorders</p><p>affecting the microcirculatory domain that escape the resolution of</p><p>angiographic techniques; and (iii) dynamic stenoses of epicardial ves-</p><p>sels caused by coronary spasm or intramyocardial bridges that are</p><p>not evident during CTA or ICA. Intracoronary pressure measure-</p><p>ments are useful in circumventing the first of these scenarios. For</p><p>diagnostic workup, patients with angina and/or myocardial ischaemia</p><p>showing coronary stenoses with non-ischaemic FFR or iwFR values</p><p>may also be labelled as having non-obstructive epicardial disease.</p><p>The presence of clear-cut anginal symptoms and abnormal non-</p><p>invasive tests in patients with non-obstructed epicardial vessels</p><p>should lead to the suspicion of a non-obstructive cause of ischaemia.</p><p>Quite often, and mainly as a result of persistence of symptoms,</p><p>patients with angina and no obstructive disease undergo multiple</p><p>diagnostic tests, including repeated coronary CTA or ICA, that con-</p><p>tribute to increased healthcare costs.409 Because diagnostic pathways</p><p>to investigate microcirculatory or vasomotor coronary disorders are</p><p>often not implemented, a final diagnosis supported by objective</p><p>Recommendations for patients with a long-standing diagnosis of chronic coronary syndromes</p><p>Recommendations for asymptomatic patients Classa Levelb</p><p>A periodic visit to a cardiovascular healthcare professional is recommended to reassess any potential change in the risk</p><p>status of patients, entailing clinical evaluation of lifestyle-modification measures, adherence to targets of cardiovascular</p><p>risk factors, and the development of comorbidities that may affect treatments and outcomes.</p><p>I C</p><p>In patients with mild or no symptoms receiving medical treatment in whom non-invasive risk stratification indicates a high</p><p>risk, and for whom revascularization is considered for improvement of prognosis, invasive coronary angiography (with</p><p>FFR when necessary) is recommended.</p><p>I C</p><p>Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C</p><p>Invasive coronary angiography is not recommended solely for risk stratification. III C</p><p>Symptomatic patients</p><p>Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed</p><p>to a reversible cause (e.g. long-standing tachycardia or myocarditis).</p><p>I C</p><p>Risk stratification is recommended in patients with new or worsening symptom levels, preferably using stress imaging or,</p><p>alternatively, exercise stress ECG.408 I B</p><p>It is recommended to expeditiously refer patients with significant worsening of symptoms for evaluation. I C</p><p>Invasive coronary angiography (with FFR/iwFR when necessary) is recommended for risk stratification in patients with</p><p>severe CAD, particularly if the symptoms are refractory to medical treatment or if they have a high-risk clinical profile.</p><p>I C</p><p>CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio;</p><p>LV = left ventricular.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>446 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..evidence is seldom reached. Owing to this, patient dismay and</p><p>depression are not rare in this clinical population.410,411 Of note, the</p><p>use</p><p>of a structured, systematic approach to explore microcirculatory</p><p>and vasomotor disorders in patients with non-obstructive CAD, as</p><p>delineated below, has been shown to increase diagnostic yield.412,413</p><p>Furthermore, an RCT, which reported in 2018, found that in patients</p><p>with non-obstructive coronary disease, tailored treatment guided by</p><p>the results of intracoronary testing [coronary flow reserve (CFR),</p><p>microcirculatory resistance, and acetylcholine testing] resulted in a</p><p>significant reduction of anginal symptoms, compared with conven-</p><p>tional, non-guided medical treatment.414</p><p>6.1 Microvascular angina</p><p>Patients with microvascular angina typically have exercise-related</p><p>angina, evidence of ischaemia in non-invasive tests, and either no</p><p>stenoses or mild-to-moderate stenoses (40�60%), revealed by</p><p>ICA or CTA, that are deemed functionally non-relevant.415 Given</p><p>the similarity of angina symptoms, a microvascular origin of angina</p><p>is typically suspected, after excluding obstructive epicardial coro-</p><p>nary stenoses, during diagnostic workup of patients with suspected</p><p>myocardial ischaemia. Regional LV wall motion abnormalities rarely</p><p>develop during exercise or stress in patients with microvascular</p><p>angina.412,416 Some patients may also have a mixed pattern of</p><p>angina, with occasional episodes at rest, particularly associated with</p><p>exposure to cold.</p><p>Secondary microvascular angina, in the absence of epicardial</p><p>obstruction, may result from cardiac or systemic conditions, including</p><p>those that cause LV hypertrophy (such as hypertrophic cardiomyop-</p><p>athy, aortic stenosis, and hypertensive heart disease) or inflammation</p><p>(such as myocarditis or vasculitis).417</p><p>6.1.1 Risk stratification</p><p>The presence of microcirculatory dysfunction in patients with CCS</p><p>entails a worse prognosis than originally thought, probably because</p><p>most recent evidence has been based on follow-up of patients in</p><p>whom abnormalities in the microcirculation have been objectively</p><p>documented with invasive or non-invasive techniques.418�423</p><p>Microcirculatory dysfunction precedes the development of epicar-</p><p>dial lesions, particularly in women,419 and is associated with impaired</p><p>outcomes. Among patients with diabetes undergoing diagnostic</p><p>workup, those without obstructive epicardial disease but with an</p><p>abnormal CFR have similarly poor long-term prognosis as those with</p><p>obstructive epicardial disease.421 In patients with non-significant cor-</p><p>onary stenoses by FFR, the presence of abnormal CFR is associated</p><p>with an excess of events in the long-term,418,422,423 particularly when</p><p>the index of microcirculatory resistance (IMR) is also abnormal.422</p><p>6.1.2 Diagnosis</p><p>The possibility of a microcirculatory origin of angina should be con-</p><p>sidered in patients with clear-cut angina, abnormal non-invasive func-</p><p>tional tests, and coronary vessels that are either normal or have mild</p><p>stenosis deemed functionally non-significant on ICA or CTA. One of</p><p>the challenges in performing a comprehensive assessment of micro-</p><p>vascular function is testing the two main mechanisms of dysfunction</p><p>separately: impaired microcirculatory conductance and arteriolar</p><p>dysregulation.424�426 Yet, outlining which of these two pathways is</p><p>affected is critically relevant in setting medical treatment to relieve</p><p>patient symptoms.414</p><p>Impaired microcirculatory conductance can be diagnosed by measuring</p><p>CFR or minimal microcirculatory resistance (the inverse of conduc-</p><p>tance). CFR can be measured non-invasively with transthoracic</p><p>Doppler echocardiography [by imaging left anterior descending</p><p>(LAD) flow],427 magnetic resonance imaging (myocardial perfusion</p><p>index),428�430 or PET.431 Microcirculatory resistance can be measured</p><p>in the catheterization laboratory by combining intracoronary pressure</p><p>with thermodilution-based data (to calculate the IMR) or Doppler</p><p>flow velocity (to calculate hyperaemic microvascular resistance or</p><p>HMR).432,433 Both intracoronary thermodilution and Doppler allow</p><p>the calculation of CFR. For decision-making purposes, values of IMR</p><p>>_25 units or CFR _25 units, and a negative acetylcholine provo-</p><p>cation test, beta-blockers, ACE inhibitors, and statins, along with</p><p>lifestyle changes and weight loss, are indicated.436,437 Patients devel-</p><p>oping ECG changes and angina in response to acetylcholine testing</p><p>but without severe epicardial vasoconstriction (all suggestive of</p><p>microvascular spasm) may be treated like vasospastic angina patients.</p><p>The effectiveness of a tailored treatment strategy was investigated in</p><p>the CorMiCa trial, which randomized 151 patients to a stratified</p><p>medical treatment (based on the results of CFR, IMR, and acetylcho-</p><p>line testing) vs. a standard-care group (including a sham interventional</p><p>diagnostic procedure). At 1 year, there was a significant difference in</p><p>angina scores favouring patients assigned to the stratified medical</p><p>treatment arm.414</p><p>ESC Guidelines 447</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>6.2 Vasospastic angina</p><p>Vasospastic angina should be suspected in patients with anginal</p><p>symptoms occurring predominantly at rest, with maintained effort</p><p>tolerance. The likelihood of vasospastic angina increases when</p><p>attacks follow a circadian pattern, with more episodes at night and</p><p>in the early morning hours. Patients are frequently younger and</p><p>have fewer cardiovascular risk factors than patients with effort</p><p>angina, except for cigarette smoking.442 Coronary vasospasm</p><p>should be also suspected in patients with patent coronary stents</p><p>and persistent angina.443,444</p><p>6.2.1 Diagnosis</p><p>The diagnosis of vasospastic angina is based on detecting transient</p><p>ischaemic ST-segment changes during an angina attack (usually at</p><p>rest). Patients with Prinzmetal angina represent a special subset in</p><p>whom resting angina is accompanied by transient ST-segment eleva-</p><p>tion.442,445 These ECG changes correlate with proximal vessel occlu-</p><p>sion and diffuse, distal subocclusive narrowing of epicardial vessels.</p><p>As most attacks of vasospastic angina are self-limiting, documentation</p><p>of these ECG changes is challenging. Ambulatory ECG monitoring,</p><p>preferably with 12 lead recording, may be helpful in patients in whom</p><p>vasospastic angina is suspected. The occurrence of ST-segment shifts</p><p>at normal heart rate supports the likelihood of myocardial ischaemia</p><p>caused by spasm. Extended Holter monitoring (for >1 week) may be</p><p>required for successful documentation of transient ST-segment</p><p>changes in these patients. Ambulatory ECG monitoring may also be</p><p>used to assess the results of</p><p>. . . . . . . . 452</p><p>8.3 Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452</p><p>8.4 Patients with refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453</p><p>9. Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454</p><p>10. Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.1 Diagnosis and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.2 Assessment of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.3 Lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.4 Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.5 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.6 Heart failure and left ventricular dysfunction . . . . . . . . . . . . . . . . 455</p><p>10.7 Patients with long-standing diagnosis of chronic</p><p>coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.8 Angina without obstructive coronary artery disease . . . . . . . . 455</p><p>10.9 Screening in asymptomatic subjects . . . . . . . . . . . . . . . . . . . . . . . . 455</p><p>10.10 Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456</p><p>10.11 Patients with refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456</p><p>11. ’What to do’ and ’what not to do’ messages from the</p><p>Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456</p><p>12. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460</p><p>13. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460</p><p>14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461</p><p>Recommendations</p><p>2019 New major recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414</p><p>Changes in major recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416</p><p>Basic biochemistry testing in the initial diagnostic management</p><p>of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . 419</p><p>Resting electrocardiogram in the initial diagnostic management</p><p>of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . 420</p><p>Ambulatory electrocardiogram monitoring in the initial</p><p>diagnostic management of patients with suspected coronary</p><p>artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420</p><p>Resting echocardiography and cardiac magnetic resonance in</p><p>the initial diagnostic management of patients with suspected</p><p>coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421</p><p>Chest X-ray in the initial diagnostic management of patients</p><p>with suspected coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421</p><p>Use of diagnostic imaging tests in the initial diagnostic</p><p>management of symptomatic patients with suspected coronary</p><p>artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426</p><p>Performing exercise electrocardiogram in the initial diagnostic</p><p>management of patients with suspected coronary artery disease . . . . 426</p><p>Recommendations for risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428</p><p>Recommendations on lifestyle management . . . . . . . . . . . . . . . . . . . . . . . 431</p><p>Recommendations on anti-ischaemic drugs in patients with</p><p>chronic coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435</p><p>Recommendations for event prevention I . . . . . . . . . . . . . . . . . . . . . . . . . . 438</p><p>Recommendations for event prevention II . . . . . . . . . . . . . . . . . . . . . . . . . 441</p><p>General recommendations for the management of patients with</p><p>cnronic coronary syndromes and symptomatic heart failure</p><p>due to ischaemic cardiomyopathy and left ventricular systolic</p><p>dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443</p><p>Recommendations for patients with a long-standing diagnosis</p><p>of chronic coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446</p><p>Investigations in patients with suspected coronary microvascular</p><p>angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448</p><p>Recommendations for investigations in patients with suspected</p><p>vasospastic angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448</p><p>Recommendations for screening for coronary artery disease in</p><p>asymptomatic subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449</p><p>Recommendations for hypertension treatment in chronic</p><p>coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>Recommendations for valvular disease in chronic coronary</p><p>syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450</p><p>Recommendations for active cancer in chronic coronary</p><p>syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451</p><p>Recommendations for diabetes mellitus in chronic coronary</p><p>syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451</p><p>Recommendations for chronic kidney disease in chronic</p><p>coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452</p><p>Recommendations for elderly patients with chronic</p><p>coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452</p><p>Recommendation for sex issues and chronic coronary</p><p>syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453</p><p>Recommendations for treatment options for refractory angina . . . . . 454</p><p>Recommendations: ’what to do’ and ’what not to do’ . . . . . . . . . . . . . . . 456</p><p>List of tables</p><p>Table 1 Classes of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412</p><p>Table 2 Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412</p><p>ESC Guidelines 409</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>Table 3 Traditional clinical classification of suspected anginal</p><p>symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418</p><p>Table 4 Grading of effort angina severity according to the</p><p>Canadian Cardiovascular Society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418</p><p>Table 5 Pre-test probabilities of obstructive coronary artery</p><p>disease in 15 815 symptomatic patients according to age, sex,</p><p>and the nature of symptoms in a pooled analysis of contemporary</p><p>data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .</p><p>medical therapy in controlling the fre-</p><p>quency of vasospastic events.</p><p>In patients with suspected vasospastic angina and documented ECG</p><p>changes, CTA or ICA is indicated to rule-out the presence of fixed</p><p>coronary stenosis. Angiographic documentation of coronary spasm</p><p>requires the use of a provocation test in the catheterization laboratory.</p><p>Given the low sensitivity of hyperventilation and the cold pressor test,</p><p>intracoronary administration of acetylcholine or ergonovine during</p><p>ICA are the preferred provocation tests.442 Both pharmacological</p><p>agents are safe, provided that they are selectively infused into the left</p><p>or right coronary artery, and that triggered spasm is readily controlled</p><p>with intracoronary nitrates. A low percentage of patients may develop</p><p>ventricular tachycardia/ventricular fibrillation or bradyarrhythmias dur-</p><p>ing the provocation test (3.2 and 2.7%, respectively), similar to that</p><p>reported during spontaneous spasm attacks (7%).446 Intravenous</p><p>administration of ergonovine for non-invasive tests should be discour-</p><p>aged due to the risk of triggering prolonged spasm in multiple vessels,</p><p>which may be very difficult to manage and can be fatal.447</p><p>A provocation test for coronary spasm is considered positive when</p><p>it triggers: (i) anginal symptoms, (ii) ischaemic ECG changes, and (iii)</p><p>severe vasoconstriction of the epicardial vessel. Should the test fail in</p><p>triggering all three components, it should be considered equivocal.442</p><p>The development of angina in response to acetylcholine injections in</p><p>the absence of angiographically evident spasm, with or without accom-</p><p>panying ST-segment changes, may indicate microvascular spasm and is</p><p>seen frequently in patients presenting with microvascular angina.445</p><p>6.2.2 Treatment</p><p>In patients with epicardial or microcirculatory vasomotor disorders,</p><p>CCBs and long-acting nitrates constitute the treatment of choice, in</p><p>addition to the control of cardiovascular risk factors and lifestyle</p><p>changes.437,445 Nifedipine has been shown to be effective in reducing</p><p>coronary spasm associated with stent implantation.444</p><p>Investigations in patients with suspected coronary micro-</p><p>vascular angina</p><p>Recommendations Classa Levelb</p><p>Guidewire-based CFR and/or microcirculatory</p><p>resistance measurements should be consid-</p><p>ered in patients with persistent symptoms, but</p><p>coronary arteries that are either angiographi-</p><p>cally normal or have moderate stenoses with</p><p>preserved iwFR/FFR.412,413</p><p>IIa B</p><p>Intracoronary acetylcholine with ECG moni-</p><p>toring may be considered during angiography,</p><p>if coronary arteries are either angiographically</p><p>normal or have moderate stenoses with pre-</p><p>served iwFR/FFR, to assess microvascular</p><p>vasospasm.412,438�440</p><p>IIb B</p><p>Transthoracic Doppler of the LAD, CMR, and</p><p>PET may be considered for non-invasive</p><p>assessment of CFR.430�432,441</p><p>IIb B</p><p>CFR = coronary flow reserve; CMR = cardiac magnetic resonance; ECG = elec-</p><p>trocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free</p><p>ratio; LAD = left anterior descending; PET = positron emission tomography.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>Recommendations for investigations in patients with</p><p>suspected vasospastic angina</p><p>Recommendations Classa Levelb</p><p>An ECG is recommended during angina if</p><p>possible.</p><p>I C</p><p>Invasive angiography or coronary CTA is rec-</p><p>ommended in patients with characteristic epi-</p><p>sodic resting angina and ST-segment changes,</p><p>which resolve with nitrates and/or calcium</p><p>antagonists, to determine the extent of under-</p><p>lying coronary disease.</p><p>I C</p><p>Ambulatory ST-segment monitoring should be</p><p>considered to identify ST-segment deviation in</p><p>the absence of increased heart rate.</p><p>IIa C</p><p>An intracoronary provocation test should be</p><p>considered to identify coronary spasm in</p><p>patients with normal findings or non-obstruc-</p><p>tive lesions on coronary arteriography and a</p><p>clinical picture of coronary spasm, to diagnose</p><p>the site and mode of spasm.412,414,438�440</p><p>IIa B</p><p>CTA = computed tomography angiography; ECG = electrocardiogram.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>448 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>7 Screening for coronary artery</p><p>disease in asymptomatic subjects</p><p>In an effort to lower the high burden of coronary deaths in asympto-</p><p>matic adults, numerous measurements of risk factors and risk markers,</p><p>as well as stress tests, are often performed as screening investigations.</p><p>The 2016 European Guidelines on CVD prevention in clinical practice</p><p>have focused on these issues in detail.15 These recommendations have</p><p>been adapted for the purpose of these Guidelines.</p><p>In general, the use of risk-estimation systems such as SCORE is</p><p>recommended (see also Figure 6). Subjects with a family history of</p><p>premature CAD should be screened for familial hypercholesterolae-</p><p>mia. Coronary calcium score, ankle-brachial index, and carotid ultra-</p><p>sound for plaque detection may provide useful information about the</p><p>atherosclerotic risk in selected patients, but routine use of bio-</p><p>markers or other imaging tests for CAD are not recommended. The</p><p>new biomarkers have incremental predictive value over classical</p><p>ones,448 but the net reclassification improvement is still only modest</p><p>(7�18%) compared, for example, with the coronary calcium score,</p><p>which has a net reclassification improvement of 66%.449</p><p>Only subjects at high event risk should be considered for further</p><p>non-invasive or invasive testing. There are no data on how to manage</p><p>asymptomatic subjects who receive testing and have a positive test</p><p>result beyond the recommendations listed in these Guidelines.</p><p>However, the principles of risk stratification, as described above for</p><p>symptomatic patients, also apply to these individuals.450 It is impor-</p><p>tant to remember that data demonstrating improved prognosis fol-</p><p>lowing appropriate management based on new biomarkers are still</p><p>lacking.</p><p>It is important to note that patients with cancer and undergoing</p><p>cancer treatment, or chronic inflammatory diseases such as inflam-</p><p>matory bowel diseases, rheumatoid arthritis, and systemic lupus</p><p>erythematosus, may deserve more intensive risk screening, counsel-</p><p>ling, and management.451�454</p><p>Persons whose occupations involve public safety (e.g. airline</p><p>pilots, or lorry or bus drivers), or who are professional or high-</p><p>profile athletes, commonly undergo periodic testing for the assess-</p><p>ment of exercise capacity and evaluation of possible heart disease,</p><p>including CAD. Although there are insufficient data to justify this</p><p>approach, these evaluations may be done for medicolegal reasons.</p><p>The threshold for performing an imaging test in such persons may</p><p>be lower than in the average patient. Otherwise, the same consid-</p><p>erations as discussed above for other asymptomatic persons apply</p><p>to these individuals.</p><p>Recommendations for screening for coronary artery disease in asymptomatic subjects</p><p>Recommendations Classa Levelb</p><p>Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults >40 years</p><p>of age without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia.</p><p>I C</p><p>Assessment of family history of premature CVD (defined as a fatal or non-fatal CVD event, or/and established diagnosis of</p><p>CVD in first-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as</p><p>part of cardiovascular risk assessment.</p><p>I C</p><p>It is recommended that all individuals aged</p><p>Atherosclerotic plaque detection by carotid artery ultrasound may be considered as a risk modifierc in the cardiovascular</p><p>risk assessment of asymptomatic subjects.458 IIb B</p><p>ABI may be considered as a risk modifierc in cardiovascular risk assessment.459 IIb B</p><p>In high-risk asymptomatic adults (with diabetes, a strong family history of CAD, or when previous risk-assessment tests</p><p>suggest a high risk of CAD), functional imaging or coronary CTA may be considered for cardiovascular risk assessment.</p><p>IIb C</p><p>In asymptomatic adults (including sedentary adults considering starting a vigorous exercise programme), an exercise ECG</p><p>may be considered for cardiovascular risk assessment, particularly when attention is paid to non-ECG markers such as</p><p>exercise capacity.</p><p>IIb C</p><p>Carotid ultrasound IMT for cardiovascular risk assessment is not recommended.460 III A</p><p>In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia are not indicated for fur-</p><p>ther diagnostic assessment.</p><p>III C</p><p>Routine assessment of circulating biomarkers is not recommended for cardiovascular risk stratification.448,449,461,462 III B</p><p>ABI = ankle-brachial index; CAD = coronary artery disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG =</p><p>electrocardiogram; IMT = intima-media thickness; SCORE = Systematic COronary Risk Evaluation.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>cReclassifies patients better into low- or high-risk groups.</p><p>ESC Guidelines 449</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..8 Chronic coronary syndromes in</p><p>specific circumstances</p><p>8.1 Cardiovascular comorbidities</p><p>8.1.1 Hypertension</p><p>Hypertension is the most prevalent cardiovascular risk factor and is</p><p>closely associated with CCS. Thresholds for the definition of hyperten-</p><p>sion are provided in Table 10. BP lowering can significantly reduce major</p><p>cardiovascular risk, including CHD. Meta-analysis suggests that for every</p><p>10 mmHg reduction in systolic BP, CAD can be reduced by 17%.463</p><p>More intensive BP targets (office BP _140 mmHg</p><p>and diastolic BP of >_80 mmHg, but also a systolic BP of 40 years of age and post-</p><p>menopausal women, or one or more cardio-</p><p>vascular risk factors.</p><p>I C</p><p>ICA is recommended in the evaluation of</p><p>moderate-to-severe functional mitral</p><p>regurgitation.</p><p>I C</p><p>Coronary CTA should be considered as an</p><p>alternative to coronary angiography before</p><p>valve intervention in patients with severe valv-</p><p>ular heart disease and low probability of CAD.</p><p>IIa C</p><p>PCI should be considered in patients under-</p><p>going transcatheter aortic valve implantation</p><p>and coronary artery diameter stenosis >70%</p><p>in proximal segments.</p><p>IIa C</p><p>In severe valvular heart disease, stress testing</p><p>should not be routinely used to detect CAD</p><p>because of the low diagnostic yield and poten-</p><p>tial risks.</p><p>III C</p><p>CAD = coronary artery disease; CTA = computed tomography angiography;</p><p>CVD = cardiovascular disease; ICA = invasive coronary angiography; LV = left</p><p>ventricular; PCI = percutaneous coronary intervention.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>Recommendations for hypertension treatment in chronic</p><p>coronary syndromes</p><p>Recommendations Classa Levelb</p><p>It is recommended that office BP is controlled</p><p>to target values: systolic BP 120 - 130 mmHg in</p><p>general and systolic BP 130 - 140 mmHg in</p><p>older patients (aged >65 years).463�467,470�472</p><p>I A</p><p>In hypertensive patients with a recent MI, beta-</p><p>blockers and RAS blockers are recommended.467 I A</p><p>In patients with symptomatic angina, beta-</p><p>blockers and/or CCBs are recommended.467 I A</p><p>The combination of ACE inhibitors and ARBs is</p><p>not recommended.468,469 III A</p><p>ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; BP =</p><p>blood pressure; CCB = calcium channel blocker; RAS = renin-angiotensin system.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>Table 10 Blood pressure thresholds for the definition of</p><p>hypertension with different types of blood pressure</p><p>measurement470�472</p><p>Category Systolic BP</p><p>(mmHg)</p><p>Diastolic BP</p><p>(mmHg)</p><p>Office BP >_140 and/or >_90</p><p>>_80 years of age >_160 and/or >_90</p><p>Ambulatory BP</p><p>Daytime (or awake) >_135 and/or >_85</p><p>Night-time (or asleep) >_120 and/or >_70</p><p>24 h >_130 and/or >_80</p><p>Home BP >_135 and/or >_85</p><p>BP = blood pressure.</p><p>450 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..examinations may be useful in assessing cardiac allograft vasculopathy</p><p>and plaque stability.478 Treatment options for CAD in transplant</p><p>recipients include pharmacotherapy and revascularization. PCI in the</p><p>transplanted heart has become an established therapy.479</p><p>8.2 Non-cardiovascular comorbidities</p><p>8.2.1 Cancer</p><p>Occurrence of CAD in patients with active cancer is increasing451,452</p><p>as a side effect of cancer therapy (i.e. radiotherapy to the thorax/</p><p>mediastinum, cardiotoxic chemotherapy, or immunotherapies) or a</p><p>result of extended cancer therapies in elderly individuals. CAD in</p><p>patients with active cancer is associated with challenges for clinicians</p><p>as treatment decisions should</p><p>be the subject of individualized discus-</p><p>sions based on life expectancy, additional comorbidities such as</p><p>thrombocytopenia, increased thrombosis and bleeding propensity,</p><p>and potential interactions between drugs used in CCS management</p><p>and antineoplastic drugs. In cancer patients with increased frailty, the</p><p>least invasive revascularization procedures are recommended. For</p><p>further information, see the ESC position paper on cancer treat-</p><p>ments and cardiovascular toxicity.480</p><p>8.2.2 Diabetes mellitus</p><p>Diabetes mellitus confers about a two-fold increased risk for CAD481</p><p>and, consequently, control of risk factors is recommended for the</p><p>prevention of CVD. Systolic BP in patients with diabetes should be</p><p>targeted to _50% if the baseline LCL-C is between 1.8 and 3.5 mmol/L (70 and</p><p>135 mg/dL).15 For the majority of patients with diabetes and CAD, a</p><p>target glycated HbA1c level of 40 years) with</p><p>diabetes, functional imaging or coronary CTA</p><p>may be considered for advanced cardiovascu-</p><p>lar risk assessment.491,492</p><p>IIb B</p><p>ACE = angiotensin-converting enzyme; AF = atrial fibrillation; BP = blood pres-</p><p>sure; CAD = coronary artery disease; CCS = chronic coronary syndromes; CTA</p><p>= computed tomography angiography; CVD = cardiovascular disease; ECG =</p><p>electrocardiogram; HbA1c = glycated haemoglobin; LDL-C = low-density lipo-</p><p>protein cholesterol; MI = myocardial infarction.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>cTreatment algorithm is available in the 2019 European Society of Cardiology/</p><p>European Association for the Study of Diabetes Guidelines on diabetes mellitus,</p><p>pre-diabetes, and cardiovascular diseases.16</p><p>Recommendations for active cancer in chronic coronary</p><p>syndromes</p><p>Recommendations Classa Levelb</p><p>Treatment decisions should be based on life</p><p>expectancy, additional comorbidities such as</p><p>thrombocytopenia, increased thrombosis pro-</p><p>pensity, and potential interactions between</p><p>drugs used in CCS management and antineo-</p><p>plastic agents.</p><p>I C</p><p>If revascularization is indicated in highly symp-</p><p>tomatic patients with active cancer and</p><p>increased frailty, the least invasive procedure</p><p>is recommended.</p><p>I C</p><p>CCS = chronic coronary syndromes.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>ESC Guidelines 451</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>8.2.3 Chronic kidney disease</p><p>CAD is highly prevalent in patients with CKD and a growing number</p><p>of patients undergoing PCI have concomitant CKD.493 There is a lin-</p><p>ear increase in the risk of cardiovascular mortality with decreasing</p><p>GFR.494 Medical treatment for risk-factor control (lipids, BP, and glu-</p><p>cose) can improve outcomes. Special attention during the workup</p><p>for CKD patients with suspected obstructive CAD should be paid to</p><p>the fact that angina is less common and silent ischaemia more com-</p><p>mon.495 Additionally, non-invasive stress testing shows reduced accu-</p><p>racy in patients with CKD.496 The use of an iodinated contrast agent</p><p>should be minimized to prevent further deterioration of renal func-</p><p>tion. Decisions regarding diagnostic and treatment modalities should</p><p>be made accordingly. Interestingly, patients with CKD are less likely</p><p>to receive invasive management for treatment of CAD compared</p><p>with those without, although benefits of invasive management have</p><p>been reported.497 Revascularization options in patients with CKD</p><p>include CABG and PCI. Meta-analyses suggest that CABG is associ-</p><p>ated with higher short-term risk of death, stroke, and repeat revascu-</p><p>larization, whereas PCI with a new-generation DES is associated with</p><p>a higher long-term risk of repeat revascularization.498,499 Data on</p><p>patients on haemodialysis are very limited, making generalizable</p><p>treatment recommendations difficult.</p><p>8.2.4 Elderly</p><p>Ageing predisposes patients to a high incidence and prevalence of</p><p>CAD, in both men and women. Elderly patients (age >75 years) have</p><p>the greatest mortality and morbidity risk attributable to CCS, which</p><p>is enriched by the high prevalence of comorbidities (e.g. hyperten-</p><p>sion, diabetes mellitus, CKD, etc.).505 Although the prevalence of eld-</p><p>erly patients with CAD is increasing, this population is usually</p><p>undertreated, underdiagnosed, and under-represented in clinical tri-</p><p>als. Elderly patients often present with atypical symptoms, which may</p><p>delay proper diagnosis. The treatment of CCS in the elderly is com-</p><p>plicated by a higher vulnerability to complications for both conserva-</p><p>tive and invasive strategies, such as bleeding, renal failure, and</p><p>neurological impairments, all of which require special attention. It is</p><p>recommended that radial access is used whenever possible to reduce</p><p>access-site complications, when choosing an invasive strategy for</p><p>patient management.506,507 The use of DES, compared with bare-</p><p>metal stents, in combination with a short duration of DAPT is associ-</p><p>ated with significant safety and efficacy benefits in elderly</p><p>patients.508,509</p><p>8.3 Sex</p><p>Making up</p><p>in</p><p>women, remains incompletely understood. It has become evident</p><p>that sex-related mortality differences are particularly apparent in</p><p>younger patients, typically those aged _3 months)</p><p>due to established reversible ischaemia in the presence of obstructive</p><p>CAD, which cannot be controlled by escalating medical therapy with</p><p>the use of second- and third-line pharmacological agents, bypass</p><p>grafting, or stenting including PCI of chronic total coronary occlusion.</p><p>Incidence is growing with more advanced CAD, multiple comorbid-</p><p>ities, and ageing of the population. The quality of life of patients with</p><p>refractory angina is poor, with frequent hospitalization and a high</p><p>level of resource utilization. The number of potential treatment</p><p>options is increasing, but the level of evidence in support of their</p><p>safety and efficacy varies from non-existent (in the case of transmyo-</p><p>cardial laser application) to promising. RCTs with endpoints such as</p><p>the severity and frequency of angina, as well as quality of life, are</p><p>obviously needed, along with safety metrics. To confirm treatment</p><p>efficacy, trials with a sham-controlled design are desirable, a significant</p><p>placebo effect being part of the therapeutic effect. Patients with</p><p>refractory angina are best treated in dedicated ‘angina clinics’ by mul-</p><p>tidisciplinary teams experienced in selecting the most suitable thera-</p><p>peutic approach in the individual patient based on an accurate</p><p>diagnosis of the mechanisms of the pain syndrome. Once conven-</p><p>tional anti-ischaemic targets have been exhausted (through an</p><p>increase in nutrient blood flow delivery and/or reduction in oxygen</p><p>consumption), novel therapies can be ranked by mechanism of</p><p>action: promotion of collateral growth, transmural redistribution of</p><p>blood flow, and neuromodulation of the cardiac pain syndrome</p><p>(Table 11).</p><p>Both the STARTSTIM and RENEW (Efficacy and Safety of</p><p>Targeted Intramyocardial Delivery of Auto CD34þ Stem Cells for</p><p>Improving Exercise Capacity in Subjects With Refractory Angina) tri-</p><p>als were underpowered due to premature study termination. Of</p><p>note, a patient-level pooled analysis of 304 patients included in three</p><p>double-blind, cell therapy, placebo-controlled trials, among which</p><p>was the RENEW trial, showed that active treatment with autologous</p><p>haematopoietic cells had significant effects on exercise time and</p><p>angina frequency.528</p><p>Based on positive results from two RCTs in small groups of</p><p>patients, both enhanced external counterpulsation and the coronary</p><p>sinus reducer device represent alternative options in patients with</p><p>refractory angina, which is resistant after having exhausted all options</p><p>for medical therapy and mechanical revascularization. Controlled</p><p>coronary sinus narrowing with the implantation of a large stainless-</p><p>steel device increases coronary sinus pressure, leading to improved</p><p>perfusion in the LAD territory.</p><p>Total reported experience with all novel therapeutic options</p><p>remains limited, both regarding the number of treated patients and</p><p>the duration of follow-up. Larger RCTs are required to define the</p><p>role of each treatment modality for specific subgroups, to decrease</p><p>non-responder rates and ascertain benefit beyond potential placebo</p><p>effects.</p><p>Recommendation for sex issues and chronic coronary</p><p>syndromes</p><p>Recommendation Classa Levelb</p><p>Hormone replacement therapy is not recom-</p><p>mended for risk reduction in post-menopausal</p><p>women.</p><p>III C</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>Table 11 Potential treatment options for refractory angina and summary of trial data</p><p>Therapy Type of therapy RCT Type of control group Number of</p><p>patients enrolled</p><p>External counterpulsation Enhanced external counterpulsation MUST524 Sham 139</p><p>Extracorporeal shockwave Low-energy extracorporeal shockwave therapy Not available Not available —</p><p>Coronary sinus constriction Reducer device COSIRA525 Sham 104</p><p>Neuromodulation Spinal cord stimulation STARTSTIM526 Not available 68</p><p>Transcutaneous electrical neural stimulation Not available Not available —</p><p>Subcutaneous electrical neural stimulation Not available Not available —</p><p>Sympathectomy Denby et al.527 Placebo 65</p><p>Gene therapy Adenovirus fibroblast growth factor 5 Not available Not available —</p><p>Autologous cell therapy Mononuclear bone marrow-derived</p><p>haematopoietic progenitor cells</p><p>RENEW528 Placebo 112</p><p>RCT = randomized clinical trial.</p><p>ESC Guidelines 453</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>9 Key messages</p><p>(1) Careful evaluation of patient history, including the characterization</p><p>of anginal symptoms, and evaluation of risk factors and manifesta-</p><p>tions of CVD, as well as proper physical examination and basic</p><p>testing, are crucial for</p><p>the diagnosis and management of CCS.</p><p>(2) Unless obstructive CAD can be excluded based on clinical evalua-</p><p>tion alone, either non-invasive functional imaging or anatomical</p><p>imaging using coronary CTA may be used as the initial test to rule-</p><p>out or establish the diagnosis of CCS.</p><p>(3) Selection of the initial non-invasive diagnostic test is based on the</p><p>PTP, the test’s performance in ruling-in or ruling-out obstructive</p><p>CAD, patient characteristics, local expertise, and the availability of</p><p>the test.</p><p>(4) For revascularization decisions, both anatomy and functional eval-</p><p>uation are to be considered. Either non-invasive or invasive func-</p><p>tional evaluation is required for the assessment of myocardial</p><p>ischaemia associated with angiographic stenosis, unless very high</p><p>grade (>90% diameter stenosis).</p><p>(5) Assessment of risk serves to identify CCS patients at high event risk</p><p>who are projected to derive prognostic benefit from revasculariza-</p><p>tion. Risk stratification includes the assessment of LV function.</p><p>(6) Patients at high event risk should undergo invasive investigation for</p><p>consideration of revascularization, even if they have mild or no</p><p>symptoms.</p><p>(7) Implementation of healthy lifestyle behaviours decreases the risk</p><p>of subsequent cardiovascular events and mortality, and is addi-</p><p>tional to appropriate secondary prevention therapy. Clinicians</p><p>should advise on and encourage necessary lifestyle changes in</p><p>every clinical encounter.</p><p>(8) Cognitive behavioural interventions such as supporting patients to</p><p>set realistic goals, self-monitor, plan how to implement changes</p><p>and deal with difficult situations, set environmental cues, and</p><p>engage social support are effective interventions for behaviour</p><p>change.</p><p>(9) Multidisciplinary teams can provide patients with support to make</p><p>healthy lifestyle changes, and address challenging aspects of behav-</p><p>iour and risk.</p><p>(10) Anti-ischaemic treatment must be adapted to the individual patient</p><p>based on comorbidities, co-administered therapies, expected tol-</p><p>erance and adherence, and patient preferences. The choice of</p><p>anti-ischaemic drugs to treat CCS should be adapted to the</p><p>patient’s heart rate, BP, and LV function.</p><p>(11) Beta-blockers and/or CCBs remain the first-line drugs in patients</p><p>with CCS. Beta-blockers are recommended in patients with LV</p><p>dysfunction or HF with reduced ejection fraction.</p><p>(12) Long-acting nitrates provoke tolerance with loss of efficacy. This</p><p>requires prescription of a daily nitrate-free or nitrate-low interval</p><p>of�10�14 h.</p><p>(13) Antithrombotic therapy is a key part of secondary prevention in</p><p>patients with CCS and warrants careful consideration. Patients</p><p>with a previous MI, who are at high risk of ischaemic events and</p><p>low risk of fatal bleeding, should be considered for long-term</p><p>DAPT with aspirin and either a P2Y12 inhibitor or very low-dose</p><p>rivaroxaban, unless they have an indication for an OAC such as</p><p>AF.</p><p>(14) Statins are recommended in all patients with CCS. ACE inhibitors</p><p>(or ARBs) are recommended in the presence of HF, diabetes, or</p><p>hypertension and should be considered in high-risk patients.</p><p>(15) Proton pump inhibitors are recommended in patients receiving</p><p>aspirin or combination antithrombotic therapy who are at high</p><p>risk of gastrointestinal bleeding.</p><p>(16) Efforts should be made to explain to patients the importance of</p><p>evidence-based prescriptions to increase adherence to treatment,</p><p>and repeated therapeutic education is essential in every clinical</p><p>encounter.</p><p>(17) Patients with a long-standing diagnosis of CCS should undergo</p><p>periodic visits to assess potential changes in risk status, adherence</p><p>to treatment targets, and the development of comorbidities.</p><p>Repeat stress imaging or ICA with functional testing is recom-</p><p>mended in the presence of worsening symptoms and/or increased</p><p>risk status.</p><p>(18) Assessment of myocardial and valvular function and dimensions, as</p><p>well as a functional test to rule-out significant myocardial silent</p><p>ischaemia, may be contemplated every 3�5 years in asymptomatic</p><p>patients with a long-standing diagnosis of CCS.</p><p>Recommendations for treatment options for refractory angina</p><p>Recommendations Classa Levelb</p><p>Enhanced external counterpulsation may be considered for symptom relief in patients with debilitating angina refractory</p><p>to optimal medical and revascularization strategies.524 IIb B</p><p>A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refrac-</p><p>tory to optimal medical and revascularization strategies.525 IIb B</p><p>Spinal cord stimulation may be considered to ameliorate symptoms and quality of life in patients with debilitating angina</p><p>refractory to optimal medical and revascularization strategies.526 IIb B</p><p>Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical</p><p>and revascularization strategies.529 III A</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>454 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>(19) An assessment of coronary vasomotor function should be consid-</p><p>ered in patients with non-significant epicardial CAD and objective</p><p>evidence of ischaemia.</p><p>10 Gaps in the evidence</p><p>10.1 Diagnosis and assessment</p><p>More information on the effects of various risk factors, biomarkers,</p><p>and comorbidities on the PTP of obstructive CAD is needed.</p><p>Adequately powered RCTs are needed to compare the effectiveness</p><p>of different diagnostic strategies, and to evaluate how to best inte-</p><p>grate diagnostic tests in patient care in terms of clinical outcomes and</p><p>the use of healthcare resources.</p><p>10.2 Assessment of risk</p><p>Studies should address whether an initial invasive strategy, in addition</p><p>to optimal medical therapy in patients with CCS and inducible ischae-</p><p>mia by non-invasive testing, improves outcomes. Larger trials are</p><p>needed to verify the utility of systematic assessment of biomarkers in</p><p>patients with suspected obstructive CAD.</p><p>10.3 Lifestyle management</p><p>Research regarding the most effective methods to support healthy</p><p>lifestyle behaviours in brief or very brief clinical encounters, and sus-</p><p>tain medication and lifestyle behaviour adherence over time, is</p><p>needed. The cardiovascular effects of newer e-cigarettes over the</p><p>long-term remain unknown, as does their effectiveness in smoking</p><p>cessation.</p><p>The relative benefits of high-intensity interval training vs.</p><p>moderate-intensity exercise in patients with CCS should be further</p><p>evaluated. The benefits of decreasing sedentary behaviour, and the</p><p>most appropriate ‘dose’ and type of physical activity in patients with</p><p>CCS, are unknown, as are the effectiveness and cost-effectiveness of</p><p>increasing cardiac rehabilitation participation among patients with</p><p>CCS.</p><p>10.4 Pharmacological management</p><p>The need for and duration of beta-blocker therapy following MI to</p><p>maintain a protective effect on cardiac events in the absence of LV</p><p>systolic dysfunction are unknown.</p><p>In patients with CCS and without a previous MI, it remains to be</p><p>determined whether current anti-ischaemic drugs improve</p><p>prognosis.</p><p>Whether the initial use of second-line anti-ischaemic therapy (i.e.</p><p>long-acting nitrates, ranolazine, nicorandil, ivabradine, or trimetazi-</p><p>dine) alone or in combination with a first-line drug (i.e. beta-blocker</p><p>or CCB) is superior to the combination of a beta-blocker with a CCB</p><p>to control anginal symptoms and myocardial ischaemia in patients</p><p>with CCS remains to be proven.</p><p>The efficacy and safety of aspirin or an alternative antithrombotic</p><p>therapy in patients with a mild extent of atherosclerotic disease, such</p><p>as that discovered</p><p>by coronary CTA, requires further assessment,</p><p>including the effect on cancer rates as well as cardiovascular events.</p><p>The optimal long-term antithrombotic therapy, and strategies for</p><p>individualizing this, in patients at high risk of ischaemic events is uncer-</p><p>tain. Consequently, clinical studies comparing the efficacy and safety</p><p>of aspirin þ P2Y12 inhibitor with aspirin þ factor Xa inhibitor are</p><p>warranted to determine which subgroups may be preferentially</p><p>treated with one or other strategy. The potential clinical benefit of</p><p>ticagrelor monotherapy, while stopping aspirin, remains unproved at</p><p>present.</p><p>The role of biomarkers in stratifying patients’ risk of ischaemic</p><p>events and bleeding requires clarification, including the role of growth</p><p>differentiation factor-15 in guiding the risk of bleeding with DAPT. It</p><p>is uncertain what effect novel lipid-lowering strategies will have on</p><p>the net clinical benefit of DAPT, with similar implications of other</p><p>strategies such as intensive BP lowering and, potentially in the future,</p><p>selective anti-inflammatory therapies.</p><p>10.5 Revascularization</p><p>Further studies, including RCTs, are needed to assess the value of</p><p>functional vs. anatomical guidance for CABG. The concept of com-</p><p>plete revascularization and its effect on prognosis needs to be re-</p><p>evaluated by prospective comparisons of functional vs. anatomical</p><p>guidance for stenting on the one hand, and bypass on the other. Of</p><p>note, none of the RCTs comparing PCI with CABG to date have</p><p>used combined anatomical and functional guidance for PCI, a strategy</p><p>that is suggested to significantly improve outcomes of PCI (Syntax II</p><p>registry).</p><p>10.6 Heart failure and left ventricular</p><p>dysfunction</p><p>Most of the evidence from RCTs supporting the recommendations</p><p>for the use of drugs and devices in patients with chronic heart failure</p><p>is based on cohorts with stable ischaemic heart disease and reduced</p><p>LV function. However, patients with CCS requiring acute or chronic</p><p>mechanical support are largely excluded from clinical trials, and the</p><p>optimal management of such patients with drugs and devices during</p><p>episodes of acute decompensation has not been adequately</p><p>addressed.</p><p>10.7 Patients with long-standing diagno-</p><p>sis of chronic coronary syndromes</p><p>The incremental value of using risk scores to serially evaluate</p><p>patients’ risks, and more importantly to adjust the intensity of treat-</p><p>ment, remains to be determined.</p><p>The optimal time intervals for serial visits remain to be</p><p>determined.</p><p>10.8 Angina without obstructive</p><p>coronary artery disease</p><p>Development of safe and efficacious novel pharmacological agents</p><p>for this indication remains an unmet need.</p><p>10.9 Screening in asymptomatic subjects</p><p>Further studies on biomarkers and imaging tests for screening of</p><p>CAD in asymptomatic subjects are needed. Furthermore, there are</p><p>limited data on how to manage asymptomatic subjects who receive</p><p>testing and have a positive test result, as evidence demonstrating</p><p>improved prognosis following appropriate management is still</p><p>lacking.</p><p>ESC Guidelines 455</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..10.10 Comorbidities</p><p>The role of PCI in patients with aortic stenosis remains undetermined</p><p>with respect to the indication for coronary revascularization and tim-</p><p>ing vs. valve intervention. Further information is needed on how to</p><p>adapt cardiovascular therapies in patients with chronic inflammatory</p><p>diseases.</p><p>10.11 Patients with refractory angina</p><p>Larger RCTs and registries are required to define the role of additional</p><p>treatment modalities for specific subgroups, to decrease non-</p><p>responder rates and ascertain benefit beyond potential placebo effects.</p><p>Recommendations: ‘what to do’ and ‘what not to do’ Classa Levelb</p><p>Basic biochemistry testing in the initial diagnostic management of patients with suspected CAD</p><p>If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or</p><p>ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.</p><p>I A</p><p>The following blood tests are recommended in all patients:</p><p>• Full blood count (including haemoglobin); I B</p><p>• Creatinine measurement and estimation of renal function; I A</p><p>• A lipid profile (including LDL-C). I A</p><p>It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-</p><p>mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c</p><p>and fasting plasma glucose results are inconclusive.</p><p>I B</p><p>Assessment of thyroid function is recommended in cases where there is clinical suspicion of thyroid disorders. I C</p><p>Resting ECG in the initial diagnostic management of patients with suspected CAD</p><p>A resting 12 lead ECG is recommended in all patients with chest pain without obvious non-cardiac cause. I C</p><p>A resting 12 lead ECG is recommended in all patients during or immediately after an episode of angina suspected to indi-</p><p>cate clinical instability of CAD.</p><p>I C</p><p>ST-segment alterations recorded during supraventricular tachyarrhythmias should not be used as evidence of CAD. III C</p><p>Ambulatory ECG monitoring in the initial diagnostic management of patients with suspected CAD</p><p>Ambulatory ECG monitoring is recommended in patients with chest pain and suspected arrhythmias. I C</p><p>Ambulatory ECG monitoring should not be used as routine examination in patients with suspected CCS. III C</p><p>Resting echocardiography and CMR in the initial diagnostic management of patients with suspected CAD</p><p>A resting transthoracic echocardiogram is recommended in all patients for:</p><p>• Exclusion of alternative causes of angina;</p><p>• Identification of regional wall motion abnormalities suggestive of CAD;</p><p>• Measurement of LVEF for risk-stratification purposes;</p><p>• Evaluation of diastolic function.</p><p>I B</p><p>Chest X-ray in the initial diagnostic management of patients with suspected CAD</p><p>Chest X-ray is recommended for patients with an atypical presentation, signs and symptoms of heart failure, or suspicion</p><p>of pulmonary disease.</p><p>I C</p><p>Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected CAD</p><p>Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnos-</p><p>ing CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.</p><p>I B</p><p>It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD</p><p>and other patient characteristics that influence test performance, local expertise, and the availability of tests.</p><p>I C</p><p>Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-</p><p>nificance or is not diagnostic.</p><p>I B</p><p>Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and</p><p>severe symptoms refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indi-</p><p>cates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revasculariza-</p><p>tion, unless very high grade (>90% diameter stenosis).</p><p>I B</p><p>Continued</p><p>11 ‘What to do’ and ‘what not to do’ messages from the Guidelines</p><p>456 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inabil-</p><p>ity to cooperate with breath-hold commands, or any other conditions makes good image quality unlikely.</p><p>III C</p><p>Coronary calcium detection by computed tomography is not recommended to identify individuals with obstructive CAD. III C</p><p>Performing exercise ECG in the initial diagnostic management of patients with suspected CAD</p><p>Exercise ECG is recommended for the assessment of exercise</p><p>tolerance, symptoms, arrhythmias, BP response, and event</p><p>risk in selected patients.</p><p>I C</p><p>Recommendations for risk assessment</p><p>Risk stratification is recommended based on clinical assessment and the result of the diagnostic test initially employed to</p><p>make a diagnosis of CAD.</p><p>I B</p><p>Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. I C</p><p>Risk stratification, preferably using stress imaging or coronary CTA (if local expertise and availability permit), or alterna-</p><p>tively exercise stress ECG (if significant exercise can be performed and the ECG is amenable to the identification of</p><p>ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.</p><p>I B</p><p>In symptomatic patients with a high-risk clinical profile, ICA complemented by invasive physiological guidance (FFR) is rec-</p><p>ommended for cardiovascular risk stratification, particularly if the symptoms are inadequately responding to medical treat-</p><p>ment and revascularization is considered for improvement of prognosis.</p><p>I A</p><p>In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended</p><p>for patients undergoing medical treatment in whom non-invasive risk stratification indicates a high event risk and revascu-</p><p>larization is considered for the improvement of prognosis.</p><p>I A</p><p>ICA is not recommended solely for risk stratification. III C</p><p>Recommendations on lifestyle management</p><p>Improvement of lifestyle factors in addition to appropriate pharmacological management is recommended. I A</p><p>Cognitive behavioural interventions are recommended to help individuals achieve a healthy lifestyle. I A</p><p>Exercise-based cardiac rehabilitation is recommended as an effective means for patients with CCS to achieve a healthy</p><p>lifestyle and manage risk factors.</p><p>I A</p><p>Involvement of multidisciplinary healthcare professionals (cardiologists, GPs, nurses, dieticians, physiotherapists, psycholo-</p><p>gists, and pharmacists) is recommended.</p><p>I A</p><p>Psychological interventions are recommended to improve symptoms of depression in patients with CCS. I B</p><p>Annual influenza vaccination is recommended for patients with CCS, especially in the elderly. I B</p><p>Recommendations on anti-ischaemic drugs in patients with CCS</p><p>General considerations</p><p>Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with</p><p>drug(s) for event prevention.</p><p>I C</p><p>It is recommended that patients are educated about the disease, risk factors, and treatment strategy. I C</p><p>Timely review of the patient’s response to medical therapies (e.g. 2�4 weeks after drug initiation) is recommended. I C</p><p>Angina/ischaemia relief</p><p>Short-acting nitrates are recommended for immediate relief of effort angina. I B</p><p>First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms. I A</p><p>Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy or co-administration of phos-</p><p>phodiesterase inhibitors.</p><p>III B</p><p>Recommendations for event prevention</p><p>Antithrombotic therapy in patients with CCS and in sinus rhythm</p><p>Aspirin 75�100 mg daily is recommended in patients with a previous MI or revascularization. I A</p><p>Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance. I B</p><p>Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm</p><p>Aspirin 75�100 mg daily is recommended following stenting. I A</p><p>Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg, >5 days, or maintenance therapy) is recommended, in</p><p>addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (1�3</p><p>months) is indicated due to the risk or occurrence of life-threatening bleeding.</p><p>I A</p><p>Antithrombotic therapy in patients with CCS and AF</p><p>When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in pref-</p><p>erence to a VKA.</p><p>I A</p><p>Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF</p><p>and a CHA2DS2-VASc score >_2 in males and >_3 in females.</p><p>I A</p><p>Continued</p><p>ESC Guidelines 457</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC</p><p>It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent</p><p>implantation.</p><p>I C</p><p>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.,</p><p>edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy.</p><p>I A</p><p>The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C</p><p>Use of proton pump inhibitors</p><p>Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC</p><p>monotherapy who are at high risk of gastrointestinal bleeding.</p><p>I A</p><p>Lipid-lowering drugs</p><p>Statins are recommended in all patients with CCS. I A</p><p>If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended. I B</p><p>For patients at very high risk who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combi-</p><p>nation with a PCSK9 inhibitor is recommended.</p><p>I A</p><p>ACE inhibitors</p><p>ACE inhibitors (or ARBs) are recommended in the presence of other conditions (e.g. HF, hypertension, or diabetes). I A</p><p>Other drugs</p><p>Beta-blockers are recommended in patients with LV dysfunction or systolic HF. I A</p><p>General recommendations for the management of patients with CCS and symptomatic HF due to ischaemic cardiomyopathy and LV</p><p>systolic dysfunction</p><p>Recommendations for drug therapy</p><p>Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF</p><p>symptoms.</p><p>I B</p><p>Beta-blockers are recommended as an essential component of treatment due to their efficacy in both relieving angina, and</p><p>reducing morbidity and mortality in HF.</p><p>I A</p><p>ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to</p><p>improve symptoms and reduce morbidity and mortality.</p><p>I A</p><p>An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition or an angiotensin recep-</p><p>tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.</p><p>I B</p><p>An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and</p><p>beta-blocker to reduce morbidity and mortality.</p><p>I A</p><p>For devices, comorbidities, and revascularization</p><p>In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker</p><p>rather than right ventricular pacing is recommended.</p><p>I A</p><p>An implantable cardioverter-defibrillator is recommended in patients with documented ventricular dysrhythmia causing</p><p>haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF _150 ms and LBBB QRS</p><p>morphology, and with LVEF</p><p>cessation and lifestyle modification, are</p><p>recommended.</p><p>I A</p><p>Myocardial revascularization is recommended when angina persists despite treatment with antianginal drugs. I A</p><p>Recommendations for patients with a long-standing diagnosis of CCS</p><p>Asymptomatic patients</p><p>A periodic visit to a cardiovascular healthcare professional is recommended to reassess potential changes in the risk status</p><p>of patients, entailing clinical evaluation of lifestyle-modification measures, adherence to targets of cardiovascular risk fac-</p><p>tors, and the development of comorbidities that may affect treatments and outcomes.</p><p>I C</p><p>Continued</p><p>458 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>In patients with mild or no symptoms receiving medical treatment, in whom non-invasive risk stratification indicates a high</p><p>risk, and for whom revascularization is considered for improvement of prognosis, ICA (with FFR when necessary) is</p><p>recommended.</p><p>I C</p><p>Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C</p><p>ICA is not recommended solely for risk stratification. III C</p><p>Symptomatic patients</p><p>Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed</p><p>to a reversible cause (e.g. long-standing tachycardia or myocarditis).</p><p>I C</p><p>Risk stratification is recommended for patients with new or worsening symptom levels, preferably using stress imaging or,</p><p>alternatively, exercise stress ECG.</p><p>I B</p><p>It is recommended that patients with significant worsening of symptoms be expeditiously referred for evaluation. I C</p><p>ICA (with FFR/iwFR when necessary) is recommended for risk stratification in patients with severe CAD, particularly if</p><p>the symptoms are refractory to medical treatment or if they have a high-risk clinical profile.</p><p>I C</p><p>Investigations in patients with suspected vasospastic angina</p><p>An ECG is recommended during angina if possible. I C</p><p>Invasive angiography or coronary CTA is recommended in patients with characteristic episodic resting angina and ST-seg-</p><p>ment changes, which resolve with nitrates and/or calcium antagonists, to determine the extent of underlying coronary</p><p>disease.</p><p>I C</p><p>Screening for CAD in asymptomatic subjects</p><p>Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults aged >40</p><p>years without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia.</p><p>I C</p><p>Assessment of family history of premature CVD (defined as a fatal or non-fatal CVD event, and/or established diagnosis of</p><p>CVD in first-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as</p><p>part of cardiovascular risk assessment.</p><p>I C</p><p>It is recommended that all individuals aged 65 years).</p><p>I A</p><p>In hypertensive patients with a recent MI, beta-blockers and RAS blockers are recommended. I A</p><p>In patients with symptomatic angina, beta-blockers and/or CCBs are recommended. I A</p><p>The combination of ACE inhibitors and an ARB is not recommended. III A</p><p>Recommendations for valvular disease in CCS</p><p>ICA is recommended before valve surgery and any of the following: history of CVD, suspected myocardial ischaemia, LV</p><p>systolic dysfunction, in men aged >40 years and post-menopausal women, or one or more cardiovascular risk factors.</p><p>I C</p><p>ICA is recommended in the evaluation of moderate-to-severe functional mitral regurgitation. I C</p><p>In severe valvular heart disease, stress testing should not be routinely used to detect CAD because of the low diagnostic</p><p>yield and potential risks.</p><p>III C</p><p>Recommendations for active cancer in CCS</p><p>Treatment decisions should be based on life expectancy, additional comorbidities such as thrombocytopenia, increased</p><p>thrombosis propensity, and potential interactions between drugs used in CCS management and antineoplastic agents.</p><p>I C</p><p>If revascularization is indicated in highly symptomatic patients with active cancer and increased frailty, the least invasive</p><p>procedure is recommended.</p><p>I C</p><p>Recommendations for diabetes mellitus in CCS</p><p>Risk factor (BP, LDL-C, and HbA1c) control to targets is recommended in patients with CAD and diabetes mellitus. I A</p><p>In asymptomatic patients with diabetes mellitus, a periodic resting ECG is recommended for cardiovascular detection of</p><p>conduction abnormalities, AF, and silent MI.</p><p>I C</p><p>Continued</p><p>ESC Guidelines 459</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..12 Supplementary data</p><p>Supplementary Data with additional Supplementary Tables and Figures</p><p>complementing the full text—as well as section 3 on patients with angina</p><p>and/or dyspnoea, and suspected coronary artery disease—are available</p><p>on the European Heart Journal website and via the ESC website at www.</p><p>escardio.org/guidelines.</p><p>13 Appendix</p><p>Author/Task Force Member affiliations:</p><p>Stephan Achenbach, Department of Cardiology, Friedrich-</p><p>Alexander-Universit€at Erlangen-Nürnberg, Erlangen, Germany; Stefan</p><p>Agewall, Department of Medicine, Clinical Science, Oslo, Norway;</p><p>Emanuele Barbato, Advanced Biomedical Sciences, University</p><p>Federico II, Naples, Italy; Jeroen J. Bax, Cardiology, Leiden University</p><p>Medical Center, Leiden, Netherlands; Davide Capodanno,</p><p>CardioThoracic-Vascular and Transplant Department, A.O.U.</p><p>‘Policlinico-Vittorio Emanuele’, University of Catania, Catania, Italy;</p><p>Thomas Cuisset, Cardiology, CHU Timone, Marseille, France;</p><p>Christi Deaton, Public Health and Primary Care, University of</p><p>Cambridge School of Clinical Medicine, Cambridge, United Kingdom;</p><p>Kenneth Dickstein, Cardiology, Stavanger University Hospital,</p><p>University of Bergen, Stavanger, Norway; Thor Edvardsen,</p><p>Cardiology, Oslo University Hospital, Oslo, Norway; Javier Escaned,</p><p>Interventional Cardiology Unit, Hospital Clinico San Carlos, Madrid,</p><p>Spain; Christian Funck-Brentano, Department of Clinical</p><p>Pharmacology, Sorbonne Université, AP-HP, ICAN and INSERM CIC</p><p>Paris-Est, Paris, France; Bernard J. Gersh, Department of</p><p>Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of</p><p>America; Martine Gilard, Cardiology, Brest University, Brest, France;</p><p>David Hasdai, Cardiology, Rabin Medical Center Petah Tikva, Israel;</p><p>Robert Hatala, Department of Cardiology and Angiology, Slovak</p><p>Cardiovascular Institute, Slovak Medical University, Bratislava, Slovakia;</p><p>Felix Mahfoud, Internal Medicine III, Saarland University, Homburg,</p><p>Germany; Josep Masip, Cardiology Department /Intensive Care</p><p>Department, Hospital CIMA-Sanitas/Consorci Sanitari Integral/</p><p>University of Barcelona, Barcelona, Spain; Claudio Muneretto,</p><p>Cardiovascular Surgery, University of Brescia Medical School, Brescia,</p><p>Italy; Eva Prescott, Department of Cardiology, Bispebjerg University</p><p>Hospital, Copenhagen, Denmark; Antti Saraste, Heart Center, Turku</p><p>University Hospital, Turku, Finland; Robert F. Storey, Department of</p><p>Infection, Immunity and Cardiovascular Disease, University of Sheffield,</p><p>Sheffield, United Kingdom; Pavel Svitil, Cardiologic Practice, Practice</p><p>of General Cardiology, Jihlava, Czech</p><p>Republic; Marco Valgimigli,</p><p>Inselspital, University of Bern, Bern, Switzerland.</p><p>Treatment with ACE inhibitors is recommended in CCS patients with diabetes for event prevention. I B</p><p>The sodium-glucose co-transporter 2 inhibitors empagliflozin, canagliflozin, or dapagliflozin are recommended in patients</p><p>with diabetes and CVD.</p><p>I A</p><p>A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes and</p><p>CVD.</p><p>I A</p><p>Recommendations for CKD in CCS</p><p>It is recommended that risk factors are controlled to target values. I A</p><p>It is recommended that special attention be paid to potential dose adjustments of renally excreted drugs used in CCS. I C</p><p>It is recommended that the use of iodinated contrast agents is minimized in patients with severe CKD and preserved urine</p><p>production to prevent further deterioration.</p><p>I B</p><p>Recommendations for elderly patients with CCS</p><p>It is recommended that particular attention is paid to side effects of drugs, intolerance, and overdosing in elderly patients. I C</p><p>The use of DES is recommended in elderly patients. I A</p><p>Radial access is recommended in elderly patients to reduce access-site bleeding complications. I B</p><p>It is recommended that diagnostic and revascularization decisions are based on symptoms, the extent of ischaemia, frailty,</p><p>life expectancy, and comorbidities.</p><p>I C</p><p>Recommendation for sex issues and CCS</p><p>Hormone replacement therapy is not recommended for risk reduction in post-menopausal women. III C</p><p>Treatment options in refractory angina</p><p>Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical</p><p>and revascularization strategies.</p><p>III A</p><p>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 =</p><p>blood pressure; CHA2DS2-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled] � Vascular disease, Age 65�74 and Sex category [Female];</p><p>CAD = coronary artery disease; CCB = calcium channel blocker; CCS = chronic coronary syndromes; CKD = chronic kidney disease; CMR = cardiac magnetic resonance;</p><p>CRT = cardiac resynchronization therapy; CTA = computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DES = drug-eluting</p><p>stent; ECG = electrocardiogram; FFR = fractional flow reserve; GPs = general practitioners; HbA1C = glycated haemoglobin; HF = heart failure; ICA = invasive coronary</p><p>angiography; IMT = intima-media thickness; iwFR = instantaneous wave-free ratio (instant flow reserve); LBBB = left bundle branch block; LDL-C = low-density lipoprotein cho-</p><p>lesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antag-</p><p>onist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin</p><p>type 9; RAS = renin-angiotensin system; VKA = vitamin K antagonist.</p><p>aClass of recommendation.</p><p>bLevel of evidence.</p><p>460 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>http://www.escardio.org/guidelines</p><p>http://www.escardio.org/guidelines</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>ESC Committee for Practice Guidelines (CPG): Stephan</p><p>Windecker (Chairperson) (Switzerland), Victor Aboyans (France),</p><p>Colin Baigent (United Kingdom), Jean-Philippe Collet (France),</p><p>Veronica Dean (France), Victoria Delgado (Netherlands), Donna</p><p>Fitzsimons (United Kingdom), Christopher P. Gale (United</p><p>Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen</p><p>(Norway), Gerhard Hindricks (Germany), Bernard Iung (France),</p><p>Peter Jüni (Canada), Hugo A. Katus (Germany), Ulf Landmesser</p><p>(Germany), Christophe Leclercq (France), Maddalena Lettino (Italy),</p><p>Basil S. Lewis (Israel), Bela Merkely (Hungary), Christian Mueller</p><p>(Switzerland), Steffen Petersen (United Kingdom), Anna Sonia</p><p>Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi</p><p>(Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A.</p><p>Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M.</p><p>Touyz (United Kingdom).</p><p>ESC National Cardiac Societies actively involved in the review</p><p>process of the 2019 ESC Guidelines for the diagnosis and manage-</p><p>ment of chronic coronary syndromes.</p><p>Algeria: Algerian Society of Cardiology, Salim Benkhedda;</p><p>Austria: Austrian Society of Cardiology, Bernhard Metzler;</p><p>Belarus: Belorussian Scientific Society of Cardiologists, Volha</p><p>Sujayeva; Belgium: Belgian Society of Cardiology, Bernard</p><p>Cosyns; Bosnia and Herzegovina: Association of Cardiologists</p><p>of Bosnia and Herzegovina, Zumreta Kusljugic; Bulgaria: Bulgarian</p><p>Society of Cardiology, Vasil Velchev; Cyprus: Cyprus Society of</p><p>Cardiology, Georgios Panayi; Czech Republic: Czech Society of</p><p>Cardiology, Petr Kala; Denmark: Danish Society of Cardiology,</p><p>Sune Ammentorp Haahr-Pedersen; Egypt: Egyptian Society of</p><p>Cardiology, Hamza Kabil; Estonia: Estonian Society of Cardiology,</p><p>Tiia Ainla; Finland: Finnish Cardiac Society, Tomi Kaukonen;</p><p>France: French Society of Cardiology, Guillaume Cayla; Georgia:</p><p>Georgian Society of Cardiology, Zurab Pagava; Germany:</p><p>German Cardiac Society, Jochen Woehrle; Greece: Hellenic</p><p>Society of Cardiology, John Kanakakis; Hungary: Hungarian</p><p>Society of Cardiology, K�alm�an T�oth; Iceland: Icelandic Society of</p><p>Cardiology, Thorarinn Gudnason; Ireland: Irish Cardiac Society,</p><p>Aaron Peace; Israel: Israel Heart Society, Doron Aronson; Italy:</p><p>Italian Federation of Cardiology, Carmine Riccio; Kosovo</p><p>(Republic of): Kosovo Society of Cardiology, Shpend Elezi;</p><p>Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov;</p><p>Latvia: Latvian Society of Cardiology, Silvija Hansone; Lebanon:</p><p>Lebanese Society of Cardiology, Antoine Sarkis; Lithuania:</p><p>Lithuanian Society of Cardiology, Ruta Babarskiene;</p><p>Luxembourg: Luxembourg Society of Cardiology, Jean Beissel;</p><p>Malta: Maltese Cardiac Society, Andrew J. Cassar Maempel;</p><p>Moldova (Republic of): Moldavian Society of Cardiology, Valeriu</p><p>Revenco; Netherlands: Netherlands Society of Cardiology, G.J.</p><p>de Grooth; North Macedonia: Macedonian FYR Society of</p><p>Cardiology, Hristo Pejkov; Norway: Norwegian Society of</p><p>Cardiology, Vibeke Juliebø; Poland: Polish Cardiac Society, Piotr</p><p>Lipiec; Portugal: Portuguese Society of Cardiology, José Santos;</p><p>Romania: Romanian Society of Cardiology, Ovidiu Chioncel;</p><p>Russian Federation: Russian Society of Cardiology, Dmitry</p><p>Duplyakov; San Marino: San Marino Society of Cardiology, Luca</p><p>Bertelli; Serbia: Cardiology Society of Serbia, Ana Djordjevic</p><p>Dikic; Slovakia: Slovak Society of Cardiology, Martin Studen�can;</p><p>Slovenia: Slovenian Society of Cardiology, Matjaz Bunc; Spain:</p><p>Spanish Society of Cardiology, Fernando Alfonso; Sweden:</p><p>Swedish Society of Cardiology, Magnus B€ack; Switzerland: Swiss</p><p>Society of Cardiology, Michael Zellweger; Tunisia: Tunisian</p><p>Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad;</p><p>Turkey: Turkish Society of Cardiology, Aylin Yildirir; Ukraine:</p><p>Ukrainian Association of Cardiology, Yuriy Sirenko; United</p><p>Kingdom of Great Britain and Northern Ireland: British</p><p>Cardiovascular Society, Brian Clapp.</p><p>14 References</p><p>1. Williams RP, Manou-Stathopoulou V, Redwood SR, Marber MS. ‘Warm-up</p><p>Angina’: harnessing the benefits of exercise and myocardial ischaemia. Heart</p><p>2014;100:106�114.</p><p>2. Diamond GA. A clinically relevant classification of chest discomfort. J Am Coll</p><p>Cardiol 1983;1:574�575.</p><p>3. Genders TS, Steyerberg EW, Hunink</p><p>MG, Nieman K, Galema TW, Mollet NR, de</p><p>Feyter PJ, Krestin GP, Alkadhi H, Leschka S, Desbiolles L, Meijs MF, Cramer MJ,</p><p>Knuuti J, Kajander S, Bogaert J, Goetschalckx K, Cademartiri F, Maffei E, Martini C,</p><p>Seitun S, Aldrovandi A, Wildermuth S, Stinn B, Fornaro J, Feuchtner G, De Zordo</p><p>T, Auer T, Plank F, Friedrich G, Pugliese F, Petersen SE, Davies LC, Schoepf UJ,</p><p>Rowe GW, van Mieghem CA, van Driessche L, Sinitsyn V, Gopalan D, Nikolaou</p><p>K, Bamberg F, Cury RC, Battle J, Maurovich-Horvat P, Bartykowszki A, Merkely B,</p><p>Becker D, Hadamitzky M, Hausleiter J, Dewey M, Zimmermann E, Laule M.</p><p>Prediction model to estimate presence of coronary artery disease: retrospective</p><p>pooled analysis of existing cohorts. BMJ 2012;344:e3485.</p><p>4. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J,</p><p>Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V,</p><p>Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL; PROMISE</p><p>Investigators. Outcomes of anatomical versus functional testing for coronary</p><p>artery disease. N Engl J Med 2015;372:1291�1300.</p><p>5. SCOT-HEART investigators. CT coronary angiography in patients with suspected</p><p>angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-</p><p>group, multicentre trial. Lancet 2015;385:2383�2391.</p><p>6. SCOT-HEART investigators, Newby DE, Adamson PD, Berry C, Boon NA,</p><p>Dweck MR, Flather M, Forbes J, Hunter A, Lewis S, MacLean S, Mills NL, Norrie J,</p><p>Roditi G, Shah ASV, Timmis AD, van Beek EJR, Williams MC. Coronary CT</p><p>angiography and 5-year risk of myocardial infarction. N Engl J Med</p><p>2018;379:924�933.</p><p>7. Reeh J, Therming CB, Heitmann M, Hojberg S, Sorum C, Bech J, Husum D,</p><p>Dominguez H, Sehestedt T, Hermann T, Hansen KW, Simonsen L, Galatius S,</p><p>Prescott E. Prediction of obstructive coronary artery disease and prognosis in</p><p>patients with suspected stable angina. Eur Heart J 2018;40:1426�1435.</p><p>8. Cheng VY, Berman DS, Rozanski A, Dunning AM, Achenbach S, Al-Mallah M,</p><p>Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Chinnaiyan K, Chow BJ, Delago</p><p>A, Gomez M, Hadamitzky M, Hausleiter J, Karlsberg RP, Kaufmann P, Lin FY,</p><p>Maffei E, Raff GL, Villines TC, Shaw LJ, Min JK. Performance of the traditional age,</p><p>sex, and angina typicality-based approach for estimating pretest probability of</p><p>angiographically significant coronary artery disease in patients undergoing coro-</p><p>nary computed tomographic angiography: results from the multinational coronary</p><p>CT angiography evaluation for clinical outcomes: an international multicenter</p><p>registry (CONFIRM). Circulation 2011;124:2423�2432, 2421�2428.</p><p>9. Campeau L. Letter: Grading of angina pectoris. Circulation 1976;54:522�523.</p><p>10. Bosner S, Haasenritter J, Becker A, Karatolios K, Vaucher P, Gencer B, Herzig L,</p><p>Heinzel-Gutenbrunner M, Schaefer JR, Abu Hani M, Keller H, Sonnichsen AC, Baum</p><p>E, Donner-Banzhoff N. Ruling out coronary artery disease in primary care: develop-</p><p>ment and validation of a simple prediction rule. CMAJ 2010;182:1295�1300.</p><p>11. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger</p><p>MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P,</p><p>Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S. 2015 ESC</p><p>Guidelines for the management of acute coronary syndromes in patients pre-</p><p>senting without persistent ST-segment elevation: Task Force for the</p><p>Management of Acute Coronary Syndromes in Patients Presenting without</p><p>Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur</p><p>Heart J 2016;37:267�315.</p><p>12. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio</p><p>ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,</p><p>Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P. 2017</p><p>ESC Guidelines for the management of acute myocardial infarction in patients</p><p>presenting with ST-segment elevation: The Task Force for the management of</p><p>ESC Guidelines 461</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>acute myocardial infarction in patients presenting with ST-segment elevation of</p><p>the European Society of Cardiology (ESC). Eur Heart J 2018;39:119�177.</p><p>13. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis</p><p>RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J</p><p>Med 2010;362:886�895.</p><p>14. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK,</p><p>Jorgensen E, Kelbaek H, Prescott E. Stable angina pectoris with no obstructive</p><p>coronary artery disease is associated with increased risks of major adverse cardi-</p><p>ovascular events. Eur Heart J 2012;33:734�744.</p><p>15. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney</p><p>MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML,</p><p>Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N,</p><p>Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S.</p><p>2016 European Guidelines on cardiovascular disease prevention in clinical prac-</p><p>tice: The Sixth Joint Task Force of the European Society of Cardiology and</p><p>Other Societies on Cardiovascular Disease Prevention in Clinical Practice (con-</p><p>stituted by representatives of 10 societies and by invited experts)Developed</p><p>with the special contribution of the European Association for Cardiovascular</p><p>Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315�2381.</p><p>16. 2019 ESC/EASD Guidelines on diabetes, pre-diabetes, and cardiovascular dis-</p><p>eases. Eur Hear J 2019:In press.</p><p>17. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H,</p><p>Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G,</p><p>Taskinen MR, Tokgozoglu L, Verschuren WMM, Vlachopoulos C, Wood DA,</p><p>Zamorano JL, Cooney MT. 2016 ESC/EAS Guidelines for the management of</p><p>dyslipidaemias. Eur Heart J 2016;37:2999�3058.</p><p>18. Di Angelantonio E, Chowdhury R, Sarwar N, Aspelund T, Danesh J, Gudnason</p><p>V. Chronic kidney disease and risk of major cardiovascular disease and non-</p><p>vascular mortality: prospective population based cohort study. BMJ</p><p>2010;341:c4986.</p><p>19. Nitsch D, Grams M, Sang Y, Black C, Cirillo M, Djurdjev O, Iseki K, Jassal SK,</p><p>Kimm H, Kronenberg F, Oien CM, Levey AS, Levin A, Woodward M,</p><p>Hemmelgarn BR; Chronic Kidney Disease Prognosis Consortium. Associations of</p><p>estimated glomerular filtration rate and albuminuria with mortality and renal fail-</p><p>ure by sex: a meta-analysis. BMJ 2013;346:f324.</p><p>20. Lopes NH, da Silva Paulitsch F, Pereira A, Garzillo CL, Ferreira JF, Stolf N, Hueb</p><p>W. Mild chronic kidney dysfunction and treatment strategies for stable coronary</p><p>artery disease. J Thorac Cardiovasc Surg 2009;137:1443�1449.</p><p>21. Omland T, Pfeffer MA, Solomon SD, de Lemos JA, Røsjø H, �Saltyt _e Benth J,</p><p>Maggioni A, Domanski MJ, Rouleau JL, Sabatine MS, Braunwald E; PEACE</p><p>Investigators. Prognostic value of cardiac troponin I measured with a highly sensi-</p><p>tive assay in patients with stable coronary artery disease. J Am Coll Cardiol</p><p>2013;61:1240�1249.</p><p>22. Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM, Jablonski KA,</p><p>Tjora S, Domanski MJ, Gersh BJ, Rouleau JL, Pfeffer MA, Braunwald E, Prevention</p><p>of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial</p><p>Investigators. A sensitive cardiac troponin T assay in stable coronary artery dis-</p><p>ease. N Engl J Med 2009;361:2538�2547.</p><p>23. Everett BM, Brooks MM, Vlachos HE, Chaitman BR, Frye RL, Bhatt DL; BARI 2D</p><p>Study Group. Troponin and cardiac events in stable ischemic heart disease and</p><p>diabetes. N Engl J Med 2015;373:610�620.</p><p>24. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, Hashim I,</p><p>Berry JD, Das SR, Morrow</p><p>. . 422</p><p>Table 6 Definitions of high event risk for different test modalities</p><p>in patients with established chronic coronary syndromes . . . . . . . . . . . 427</p><p>Table 7 Lifestyle recommendations for patients with chronic</p><p>coronary syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429</p><p>Table 8 Healthy diet characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>Table 9 Treatment options for dual antithrombotic therapy in</p><p>combination with aspirin 75-100 mg daily in alphabetical order in</p><p>patients who have a high or moderate risk of ischaemic events,</p><p>and do not have a high bleeding risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440</p><p>Table 10 Blood pressure thresholds for definition of hypertension</p><p>with different types of blood pressure measurement . . . . . . . . . . . . . . . 450</p><p>Table 11 Potential treatment options for refractory angina and</p><p>summary of trial data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453</p><p>List of figures</p><p>Figure 1 Schematic illustration of the natural history of chronic</p><p>coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413</p><p>Figure 2 Approach for the initial diagnostic management of patients</p><p>with angina and suspected coronary artery disease . . . . . . . . . . . . . . . . . 417</p><p>Figure 3 Determinants of clinical likelihood of obstructive coronary</p><p>artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423</p><p>Figure 4 Main diagnostic pathways in symptomatic patients</p><p>with suspected obstructive coronary artery disease . . . . . . . . . . . . . . . . 424</p><p>Figure 5 Ranges of clinical likelihood of coronary artery disease</p><p>in which the test can rule-in or rule-out obstructive coronary</p><p>artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425</p><p>Figure 6 Comparison of risk assessments in asymptomatic</p><p>apparently healthy subjects (primary prevention) and patients with</p><p>established chronic coronary syndromes (secondary prevention) . . . 427</p><p>Figure 7 The five As of smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . 430</p><p>Figure 8 Suggested stepwise strategy for long-term</p><p>anti-ischaemic drug therapy in patients with chronic coronary</p><p>syndromes and specific baseline characteristics . . . . . . . . . . . . . . . . . . . . 434</p><p>Figure 9 Decision tree for patients undergoing invasive coronary</p><p>angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442</p><p>Figure 10 Proposed algorithm according to patient types</p><p>commonly observed at chronic coronary syndrome outpatient</p><p>clinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445</p><p>Abbreviations and acronyms</p><p>ABI Ankle-brachial index</p><p>ACE Angiotensin-converting enzyme</p><p>ACS Acute coronary syndrome(s)</p><p>ACTION A Coronary disease Trial Investigating Outcome</p><p>with Nifedipine gastrointestinal therapeutic system</p><p>AF Atrial fibrillation</p><p>ARB Angiotensin receptor blocker</p><p>AUGUSTUS An Open-label, 2� 2 Factorial, Randomized</p><p>Controlled, Clinical Trial to Evaluate the Safety of</p><p>Apixaban vs. Vitamin K Antagonist and Aspirin vs.</p><p>Aspirin Placebo in Patients With Atrial Fibrillation</p><p>and Acute Coronary Syndrome or Percutaneous</p><p>Coronary Intervention</p><p>BARI-2D Bypass Angioplasty Revascularization Investigation</p><p>2 Diabetes</p><p>BEAUTIFUL If Inhibitor Ivabradine in Patients with Coronary</p><p>Artery Disease and Left Ventricular Dysfunction</p><p>b.i.d. Bis in die (twice a day)</p><p>BMI Body mass index</p><p>BP Blood pressure</p><p>b.p.m. Beats per minute</p><p>CABG Coronary artery bypass grafting</p><p>CAD Coronary artery disease</p><p>CAPRIE Clopidogrel vs. Aspirin in Patients at Risk of</p><p>Ischaemic Events</p><p>CASS Coronary Artery Surgery Study</p><p>CCB Calcium channel blocker</p><p>CCS Chronic coronary syndrome(s)</p><p>CFR Coronary flow reserve</p><p>CHA2DS2-</p><p>VASc</p><p>Cardiac failure, Hypertension, Age >_75</p><p>[Doubled], Diabetes, Stroke [Doubled] �</p><p>Vascular disease, Age 65�74 and Sex category</p><p>[Female]</p><p>CHD Coronary heart disease</p><p>CI Confidence interval</p><p>CKD Chronic kidney disease</p><p>CMR Cardiac magnetic resonance</p><p>COMPASS Cardiovascular Outcomes for People Using</p><p>Anticoagulation Strategies</p><p>COURAGE Clinical Outcomes Utilizing Revascularization and</p><p>Aggressive Drug Evaluation</p><p>CPG Committee for Practice Guidelines</p><p>CRT Cardiac resynchronization therapy</p><p>CT Computed tomography</p><p>CTA Computed tomography angiography</p><p>CVD Cardiovascular disease</p><p>DAPT Dual antiplatelet therapy</p><p>DES Drug-eluting stent(s)</p><p>DHP Dihydropyridine</p><p>ECG Electrocardiogram</p><p>eGFR Estimated glomerular filtration rate</p><p>ESC European Society of Cardiology</p><p>FAME 2 Fractional Flow Reserve versus Angiography for</p><p>Multivessel Evaluation 2</p><p>FFR Fractional flow reserve</p><p>410 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>FFRCT Computed tomography-based fractional flow</p><p>reserve</p><p>GEMINI-</p><p>ACS</p><p>A Study to Compare the Safety of Rivaroxaban</p><p>Versus Acetylsalicylic Acid in Addition to Either</p><p>Clopidogrel or Ticagrelor Therapy in Participants</p><p>With Acute Coronary Syndrome</p><p>GFR Glomerular filtration rate</p><p>GLS Global longitudinal strain</p><p>GOSPEL Global secondary prevention strategies to limit</p><p>event recurrence after myocardial infarction</p><p>HbA1c Glycated haemoglobin</p><p>HF Heart failure</p><p>ICA Invasive coronary angiography</p><p>IMR Index of microcirculatory resistance</p><p>IMT Intima-media thickness</p><p>IONA Impact Of Nicorandil in Angina</p><p>iwFR Instantaneous wave-free ratio (instant flow</p><p>reserve)</p><p>LAD Left anterior descending</p><p>LBBB Left bundle branch block</p><p>LDL-C Low-density lipoprotein cholesterol</p><p>LM Left main (coronary artery)</p><p>LV Left ventricular</p><p>LVEF Left ventricular ejection fraction</p><p>MI Myocardial infarction</p><p>MRA Mineralocorticoid receptor antagonist</p><p>NOAC Non-vitamin K antagonist oral anticoagulant</p><p>NT-proBNP N-terminal pro-B-type natriuretic peptide</p><p>OAC Oral anticoagulant</p><p>o.d. Omni die (once a day)</p><p>ORBITA Objective Randomised Blinded Investigation with</p><p>optimal medical Therapy of Angioplasty in stable</p><p>angina</p><p>PAD Peripheral artery disease</p><p>PCI Percutaneous coronary intervention</p><p>PCSK9 Proprotein convertase subtilisin-kexin type 9</p><p>PEGASUS-</p><p>TIMI 54</p><p>Prevention of Cardiovascular Events in Patients</p><p>with Prior Heart Attack Using Ticagrelor</p><p>Compared to Placebo on a Background of</p><p>Aspirin�Thrombolysis in Myocardial Infarction 54</p><p>PET Positron emission tomography</p><p>PROMISE Prospective Multicenter Imaging Study for</p><p>Evaluation of Chest Pain</p><p>PTP Pre-test probability</p><p>RAS Renin-angiotensin system</p><p>RCT Randomized clinical trial</p><p>REACH Reduction of Atherothrombosis for Continued</p><p>Health</p><p>RIVER-PCI Ranolazine for Incomplete Vessel Revascularization</p><p>Post-Percutaneous Coronary Intervention</p><p>SCORE Systematic COronary Risk Evaluation</p><p>SCOT-</p><p>HEART</p><p>Scottish Computed Tomography of the HEART</p><p>SIGNIFY Study Assessing the Morbidity�Mortality Benefits</p><p>of the If Inhibitor Ivabradine in Patients with</p><p>Coronary Artery Disease</p><p>SPECT Single-photon emission computed tomography</p><p>VKA Vitamin K antagonist</p><p>1 Preamble</p><p>Guidelines summarize and evaluate available evidence with the aim of</p><p>assisting health professionals in proposing the best management</p><p>strategies for an individual patient with a given condition. Guidelines</p><p>and their recommendations should facilitate decision making of</p><p>health professionals in their daily practice. However, the final deci-</p><p>sions concerning an individual patient must be made by the responsi-</p><p>ble health professional(s) in consultation with the patient and</p><p>caregiver as appropriate.</p><p>A</p><p>DA, McGuire DK. Association of troponin T detected</p><p>with a highly sensitive assay and cardiac structure and mortality risk in the gen-</p><p>eral population. JAMA 2010;304:2503�2512.</p><p>25. van Holten TC, Waanders LF, de Groot PG, Vissers J, Hoefer IE, Pasterkamp G,</p><p>Prins MW, Roest M. Circulating biomarkers for predicting cardiovascular disease</p><p>risk; a systematic review and comprehensive overview of meta-analyses. PLoS</p><p>One 2013;8:e62080.</p><p>26. Madsen DM, Diederichsen ACP, Hosbond SE, Gerke O, Mickley H. Diagnostic</p><p>and prognostic value of a careful symptom evaluation and high sensitive troponin</p><p>in patients with suspected stable angina pectoris without prior cardiovascular</p><p>disease. Atherosclerosis 2017;258:131�137.</p><p>27. Laufer EM, Mingels AM, Winkens MH, Joosen IA, Schellings MW, Leiner T,</p><p>Wildberger JE, Narula J, Van Dieijen-Visser MP, Hofstra L. The extent of coro-</p><p>nary atherosclerosis is associated with increasing circulating levels of high sensi-</p><p>tive cardiac troponin T. Arterioscler Thromb Vasc Biol 2010;30:1269�1275.</p><p>28. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S,</p><p>Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R,</p><p>Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with</p><p>sensitive cardiac troponin assays. N Engl J Med 2009;361:858�867.</p><p>29. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S,</p><p>Warnholtz A, Frohlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB,</p><p>Lubos E, Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ,</p><p>Munzel TF, Blankenberg S. Sensitive troponin I assay in early diagnosis of acute</p><p>myocardial infarction. N Engl J Med 2009;361:868�877.</p><p>30. da Silveira AD, Ribeiro RA, Rossini AP, Stella SF, Ritta HA, Stein R, Polanczyk</p><p>CA. Association of anemia with clinical outcomes in stable coronary artery dis-</p><p>ease. Coron Artery Dis 2008;19:21�26.</p><p>31. Di Angelantonio E, Danesh J, Eiriksdottir G, Gudnason V. Renal function and risk</p><p>of coronary heart disease in general populations: new prospective study and sys-</p><p>tematic review. PLoS Med 2007;4:e270.</p><p>32. Shlipak MG, Matsushita K, Arnlov J, Inker LA, Katz R, Polkinghorne KR,</p><p>Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT;</p><p>Prognosis Consortium CKD. Cystatin C versus creatinine in determining risk</p><p>based on kidney function. N Engl J Med 2013;369:932�943.</p><p>33. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM,</p><p>Braunwald E, Sabatine MS. Association between lowering LDL-C and cardiovas-</p><p>cular risk reduction among different therapeutic interventions: a systematic</p><p>review and meta-analysis. JAMA 2016;316:1289�1297.</p><p>34. Cholesterol Treatment Trialists’ (CTT) Collaboration, Fulcher J, O’Connell R,</p><p>Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A,</p><p>Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P,</p><p>Franzosi MG, Baigent C, Keech A. Efficacy and safety of LDL-lowering therapy</p><p>among men and women: meta-analysis of individual data from 174,000 partici-</p><p>pants in 27 randomised trials. Lancet 2015;385:1397�1405.</p><p>35. Bartnik M, Ryden L, Malmberg K, Ohrvik J, Pyorala K, Standl E, Ferrari R,</p><p>Simoons M, Soler-Soler J; Euro Heart Survey Investigators. Oral glucose toler-</p><p>ance test is needed for appropriate classification of glucose regulation in patients</p><p>with coronary artery disease: a report from the Euro Heart Survey on Diabetes</p><p>and the Heart. Heart 2007;93:72�77.</p><p>36. Cohn PF, Fox KM, Daly C. Silent myocardial ischemia. Circulation</p><p>2003;108:1263�1277.</p><p>37. Androulakis A, Aznaouridis KA, Aggeli CJ, Roussakis GN, Michaelides AP,</p><p>Kartalis AN, Stougiannos PN, Dilaveris PE, Misovoulos PI, Stefanadis CI,</p><p>Kallikazaros IE. Transient ST-segment depression during paroxysms of atrial</p><p>fibrillation in otherwise normal individuals: relation with underlying coronary</p><p>artery disease. J Am Coll Cardiol 2007;50:1909�1911.</p><p>38. Guo Y, Zhang L, Wang C, Zhao Y, Chen W, Gao M, Zhu P, Yang T, Wang Y.</p><p>Medical treatment and long-term outcome of chronic atrial fibrillation in the</p><p>aged with chest distress: a retrospective analysis versus sinus rhythm. Clin Interv</p><p>Aging 2011;6:193�198.</p><p>39. Nucifora G, Schuijf JD, van Werkhoven JM, Trines SA, Kajander S, Tops LF,</p><p>Turta O, Jukema JW, Schreur JH, Heijenbrok MW, Gaemperli O, Kaufmann PA,</p><p>Knuuti J, van der Wall EE, Schalij MJ, Bax JJ. Relationship between obstructive</p><p>coronary artery disease and abnormal stress testing in patients with paroxysmal</p><p>or persistent atrial fibrillation. Int J Cardiovasc Imaging 2011;27:777�785.</p><p>40. Pradhan R, Chaudhary A, Donato AA. Predictive accuracy of ST depression dur-</p><p>ing rapid atrial fibrillation on the presence of obstructive coronary artery disease.</p><p>Am J Emerg Med 2012;30:1042�1047.</p><p>41. Forslund L, Hjemdahl P, Held C, Bjorkander I, Eriksson SV, Rehnqvist N.</p><p>Ischaemia during exercise and ambulatory monitoring in patients with stable</p><p>angina pectoris and healthy controls. Gender differences and relationships to cat-</p><p>echolamines. Eur Heart J 1998;19:578�587.</p><p>42. Davies RF, Goldberg AD, Forman S, Pepine CJ, Knatterud GL, Geller N, Sopko</p><p>G, Pratt C, Deanfield J, Conti CR. Asymptomatic Cardiac Ischemia Pilot (ACIP)</p><p>study two-year follow-up: outcomes of patients randomized to initial strategies</p><p>of medical therapy versus revascularization. Circulation 1997;95:2037�2043.</p><p>43. Stone PH, Chaitman BR, Forman S, Andrews TC, Bittner V, Bourassa MG,</p><p>Davies RF, Deanfield JE, Frishman W, Goldberg AD, MacCallum G, Ouyang P,</p><p>Pepine CJ, Pratt CM, Sharaf B, Steingart R, Knatterud GL, Sopko G, Conti CR.</p><p>Prognostic significance of myocardial ischemia detected by ambulatory electro-</p><p>cardiography, exercise treadmill testing, and electrocardiogram at rest to predict</p><p>cardiac events by one year (the Asymptomatic Cardiac Ischemia Pilot [ACIP]</p><p>study). Am J Cardiol 1997;80:1395�1401.</p><p>44. Daly C, Norrie J, Murdoch DL, Ford I, Dargie HJ, Fox K; TIBET (Total Ischaemic</p><p>Burden European Trial) study group. The value of routine non-invasive tests to</p><p>predict clinical outcome in stable angina. Eur Heart J 2003;24:532�540.</p><p>45. Daly CA, De Stavola B, Sendon JL, Tavazzi L, Boersma E, Clemens F, Danchin N,</p><p>Delahaye F, Gitt A, Julian D, Mulcahy D, Ruzyllo W, Thygesen K, Verheugt F,</p><p>Fox KM; Euro Heart Survey Investigators. Predicting prognosis in stable angina–</p><p>results from the Euro heart survey of stable angina: prospective observational</p><p>study. BMJ 2006;332:262�267.</p><p>46. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell</p><p>DJ, Rumberger JA, Ryan T, Verani MS; American Heart Association Writing</p><p>Group on Myocardial Segmentation and Registration for Cardiac Imaging.</p><p>Standardized myocardial segmentation and nomenclature for tomographic imag-</p><p>ing of the heart. A statement for healthcare professionals from the Cardiac</p><p>Imaging Committee of the Council on Clinical Cardiology of the American Heart</p><p>Association. Circulation 2002;105:539�542.</p><p>47. Eek C, Grenne B, Brunvand H, Aakhus S, Endresen K, Hol PK, Smith HJ, Smiseth</p><p>OA, Edvardsen T, Skulstad H. Strain echocardiography and wall motion score</p><p>462 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>index predicts final infarct size in patients with non-ST-segment-elevation myo-</p><p>cardial infarction. Circ Cardiovasc Imaging 2010;3:187�194.</p><p>48. Smedsrud MK, Sarvari S, Haugaa KH, Gjesdal O, Orn S, Aaberge L, Smiseth OA,</p><p>Edvardsen T. Duration of myocardial early systolic lengthening predicts the pres-</p><p>ence of significant coronary artery disease. J Am Coll Cardiol 2012;60:1086�1093.</p><p>49. Smedsrud MK, Gravning J, Omland T, Eek C, Morkrid L, Skulstad H, Aaberge L,</p><p>Bendz B, Kjekshus J, Edvardsen T. Sensitive cardiac troponins and N-terminal</p><p>pro-B-type natriuretic peptide in stable coronary artery disease: correlation with</p><p>left ventricular function as assessed by myocardial strain. Int J Cardiovasc Imaging</p><p>2015;31:967�973.</p><p>50. Biering-Sorensen T, Hoffmann S, Mogelvang R, Zeeberg Iversen A, Galatius S,</p><p>Fritz-Hansen T, Bech J, Jensen JS. Myocardial strain analysis by 2-dimensional</p><p>speckle tracking echocardiography improves diagnostics of coronary artery</p><p>stenosis in stable angina pectoris. Circ Cardiovasc Imaging 2014;7:58�65.</p><p>51. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving</p><p>knowledge. J Am Coll Cardiol 2009;54:1561�1575.</p><p>52. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF III, Dokainish H, Edvardsen T,</p><p>Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK,</p><p>Alexandru Popescu B, Waggoner AD. Recommendations for the evaluation of</p><p>left ventricular diastolic function by echocardiography: an update from the</p><p>American Society of Echocardiography and the European Association of</p><p>Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2016;17:1321�1360.</p><p>53. Steeds RP, Garbi M, Cardim N, Kasprzak JD, Sade E, Nihoyannopoulos P,</p><p>Popescu BA, Stefanidis A, Cosyns B, Monaghan M, Aakhus S, Edvardsen T,</p><p>Flachskampf F, Galiuto L, Athanassopoulos G, Lancellotti P; 2014�2016 EACVI</p><p>Scientific Documents Committee. EACVI appropriateness criteria for the use of</p><p>transthoracic echocardiography in adults: a report of literature and current prac-</p><p>tice review. Eur Heart J Cardiovasc Imaging 2017;18:1191�1204.</p><p>54. Senior R, Becher H, Monaghan M, Agati L, Zamorano J, Vanoverschelde JL,</p><p>Nihoyannopoulos P, Edvardsen T, Lancellotti P; EACVI Scientific Documents</p><p>Committee for 2014�16 and 2016�18. Clinical practice of contrast</p><p>echocardiography: recommendation by the European Association of</p><p>Cardiovascular Imaging (EACVI) 2017. Eur Heart J Cardiovasc Imaging 2017;18:</p><p>1205�1205af.</p><p>55. Greenwood JP, Ripley DP, Berry C, McCann GP, Plein S, Bucciarelli-Ducci C,</p><p>Dall’Armellina E, Prasad A, Bijsterveld P, Foley JR, Mangion K, Sculpher M, Walker</p><p>S, Everett CC, Cairns DA, Sharples LD, Brown JM; CE-MARC 2 Investigators.</p><p>Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion</p><p>scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the</p><p>CE-MARC 2 randomized clinical trial. JAMA 2016;316:1051�1060.</p><p>56. Motwani M, Swoboda PP, Plein S, Greenwood JP. Role of cardiovascular mag-</p><p>netic resonance in the management of patients with stable coronary artery dis-</p><p>ease. Heart 2018;104:888�894.</p><p>57. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow</p><p>RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to</p><p>identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445�1453.</p><p>58. Vitarelli A, Tiukinhoy S, Di Luzio S, Zampino M, Gheorghiade M. The role of</p><p>echocardiography in the diagnosis and management of heart failure. Heart Fail</p><p>Rev 2003;8:181�189.</p><p>59. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagno-</p><p>sis of coronary-artery disease. N Engl J Med 1979;300:1350�1358.</p><p>60. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A,</p><p>Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot</p><p>JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R,</p><p>Taggart DP, van der Wall EE, Vrints CJ. 2013 ESC guidelines on the management</p><p>of stable coronary artery disease: the Task Force on the management of stable</p><p>coronary artery disease of the European Society of Cardiology. Eur Heart J</p><p>2013;34:2949�3003.</p><p>61. Genders TS, Steyerberg EW, Alkadhi H, Leschka S, Desbiolles L, Nieman K,</p><p>Galema TW, Meijboom WB, Mollet NR, de Feyter PJ, Cademartiri F, Maffei E,</p><p>Dewey M, Zimmermann E, Laule M, Pugliese F, Barbagallo R, Sinitsyn V, Bogaert</p><p>J, Goetschalckx K, Schoepf UJ, Rowe GW, Schuijf JD, Bax JJ, de Graaf FR, Knuuti</p><p>J, Kajander S, van Mieghem CA, Meijs MF, Cramer MJ, Gopalan D, Feuchtner G,</p><p>Friedrich G, Krestin GP, Hunink MG, CAD Consortium. A clinical prediction</p><p>rule for the diagnosis of coronary artery disease: validation, updating, and exten-</p><p>sion. Eur Heart J 2011;32:1316�1330.</p><p>62. Foldyna B, Udelson JE, Karady J, Banerji D, Lu MT, Mayrhofer T, Bittner DO,</p><p>Meyersohn NM, Emami H, Genders TSS, Fordyce CB, Ferencik M, Douglas PS,</p><p>Hoffmann U. Pretest probability for patients with suspected obstructive coro-</p><p>nary artery disease: re-evaluating Diamond-Forrester for the contemporary era</p><p>and clinical implications: insights from the PROMISE trial. Eur Heart J Cardiovasc</p><p>Imaging 2018;20:574�581.</p><p>63. Adamson PD, Newby DE, Hill CL, Coles A, Douglas PS, Fordyce CB.</p><p>Comparison of international guidelines for assessment of suspected stable angina:</p><p>insights from the PROMISE and SCOT-HEART. JACC Cardiovasc Imaging</p><p>2018;11:1301�1310.</p><p>64. Juarez-Orozco LE, Saraste A, Capodanno D, Prescott E, Ballo H, Bax JJ, Wijns</p><p>W, Knuuti J. Impact of a decreasing pre-test probability on the performance of</p><p>diagnostic tests for coronary artery disease. Eur Heart J Cardiovasc Imaging</p><p>2019;doi: 10.1093/ehjci/jez054.</p><p>65. Versteylen MO, Joosen IA, Shaw LJ, Narula J, Hofstra L. Comparison of</p><p>Framingham, PROCAM, SCORE, and Diamond Forrester to predict coronary</p><p>atherosclerosis and cardiovascular events. J Nucl Cardiol 2011;18:904�911.</p><p>66. Fordyce CB, Douglas PS, Roberts RS, Hoffmann U, Al-Khalidi HR, Patel MR,</p><p>Granger CB, Kostis J, Mark DB, Lee KL, Udelson JE; Prospective Multicenter</p><p>Imaging Study for Evaluation of Chest Pain (PROMISE) Investigators.</p><p>Identification of patients with stable chest pain deriving minimal value from non-</p><p>invasive testing: the PROMISE minimal-risk tool, a secondary analysis of a</p><p>randomized clinical trial. JAMA Cardiol 2017;2:400�408.</p><p>67. Jensen JM, Voss M, Hansen VB, Andersen LK, Johansen PB, Munkholm H,</p><p>Norgaard BL. Risk stratification of patients suspected of coronary artery disease:</p><p>comparison of five different models. Atherosclerosis 2012;220:557�562.</p><p>68. Sharma A, Sekaran NK, Coles A, Pagidipati NJ, Hoffmann U, Mark DB, Lee KL,</p><p>Al-Khalidi HR, Lu MT, Pellikka PA, Trong QA, Douglas PS. Impact of diabetes</p><p>mellitus on the evaluation of stable chest pain patients: insights from the</p><p>PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)</p><p>trial. J Am Heart Assoc 2017;6:e007019.</p><p>69. Budoff MJ, Mayrhofer T, Ferencik M, Bittner D, Lee KL, Lu MT, Coles A, Jang J,</p><p>Krishnam M, Douglas PS, Hoffmann U; PROMISE Investigators. Prognostic value</p><p>of coronary artery calcium in the PROMISE study (Prospective Multicenter</p><p>Imaging Study for Evaluation of Chest Pain). Circulation 2017;136:1993�2005.</p><p>70. Villines TC, Hulten EA, Shaw LJ, Goyal M, Dunning A, Achenbach S, Al-Mallah M,</p><p>Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng VY,</p><p>Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin</p><p>FY, Maffei E, Raff GL, Min JK; CONFIRM Registry Investigators. Prevalence and</p><p>severity of coronary artery disease and adverse events among symptomatic</p><p>patients with coronary artery calcification scores of zero undergoing coronary</p><p>computed tomography angiography: results from the CONFIRM (Coronary CT</p><p>Angiography Evaluation for Clinical Outcomes: An International Multicenter)</p><p>registry. J Am Coll Cardiol 2011;58:2533�2540.</p><p>71. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N,</p><p>Mobius-Winkler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T,</p><p>Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N,</p><p>Johnson JB, Juni P, Fearon WF; FAME 2 Trial Investigators. Fractional flow</p><p>reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J</p><p>Med 2012;367:991�1001.</p><p>72. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, Klauss V,</p><p>Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon</p><p>WF; FAME Study Investigators. Fractional flow reserve versus angiography for</p><p>guiding percutaneous coronary intervention. N Engl J Med 2009;360:213�224.</p><p>73. Knuuti J, Ballo H, Juarez-Orozco LE, Saraste A, Kolh P, Rutjes AWS, Juni P,</p><p>Windecker S, Bax JJ, Wijns W. The performance of non-invasive tests to rule-in</p><p>and rule-out significant coronary artery stenosis in patients with stable angina: a</p><p>meta-analysis focused on post-test disease probability. Eur Heart J</p><p>2018;39:3322�3330.</p><p>74. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN,</p><p>Maccarthy PA, Van’t Veer M, Pijls NH. Angiographic versus functional severity of</p><p>coronary artery stenoses in the FAME study fractional flow reserve versus</p><p>angiography in multivessel evaluation. J Am Coll Cardiol 2010;55:2816�2821.</p><p>75. Hoffmann U, Ferencik M, Udelson JE, Picard MH, Truong QA, Patel MR, Huang</p><p>M, Pencina M, Mark DB, Heitner JF, Fordyce CB, Pellikka PA, Tardif JC, Budoff M,</p><p>Nahhas G, Chow B, Kosinski AS, Lee KL, Douglas PS; PROMISE Investigators.</p><p>Prognostic value of noninvasive cardiovascular testing in patients with stable</p><p>chest pain: insights from the PROMISE trial (Prospective Multicenter Imaging</p><p>Study for Evaluation of Chest Pain). Circulation 2017;135:2320�2332.</p><p>76. Siontis GC, Mavridis D, Greenwood JP, Coles B, Nikolakopoulou A, Juni P,</p><p>Salanti G, Windecker S. Outcomes of non-invasive diagnostic modalities for the</p><p>detection of coronary artery disease: network meta-analysis of diagnostic rando-</p><p>mised controlled trials. BMJ 2018;360:k504.</p><p>77. Collet C, Onuma Y, Andreini D, Sonck J, Pompilio G, Mushtaq S, La Meir M,</p><p>Miyazaki Y, de Mey J, Gaemperli O, Ouda A, Maureira JP, Mandry D, Camenzind</p><p>E, Macron L, Doenst T, Teichgraber U, Sigusch H, Asano T, Katagiri Y, Morel</p><p>MA, Lindeboom W, Pontone G, Luscher TF, Bartorelli AL, Serruys PW.</p><p>Coronary computed tomography angiography for heart team decision-making in</p><p>multivessel coronary artery disease. Eur Heart J 2018;39:3689�3698.</p><p>78. Lubbers M, Dedic A, Coenen A, Galema T, Akkerhuis J, Bruning T, Krenning B,</p><p>Musters P, Ouhlous M, Liem A, Niezen A, Hunink M, de Feijter P, Nieman K.</p><p>Calcium imaging and selective computed tomography angiography in comparison</p><p>to functional testing for suspected coronary artery disease: the multicentre,</p><p>randomized CRESCENT trial. Eur Heart J 2016;37:1232�1243.</p><p>79. Zacharias K, Ahmed A, Shah BN, Gurunathan S, Young G, Acosta D, Senior R.</p><p>Relative clinical and economic impact of exercise echocardiography vs. exercise</p><p>ESC Guidelines 463</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>electrocardiography, as first line investigation in patients without known coro-</p><p>nary artery disease and new stable angina: a randomized prospective study. Eur</p><p>Heart J Cardiovasc Imaging 2017;18:195�202.</p><p>80. Williams MC, Hunter A, Shah ASV, Assi V, Lewis S, Smith J, Berry C, Boon NA,</p><p>Clark E, Flather M, Forbes J, McLean S, Roditi G, van Beek EJR, Timmis AD,</p><p>Newby DE; SCOT-HEART Investigators. Use of coronary computed tomo-</p><p>graphic angiography to guide management of patients with coronary disease.</p><p>J Am Coll Cardiol 2016;67:1759�1768.</p><p>81. Jorgensen ME, Andersson C, Norgaard BL, Abdulla J, Shreibati JB, Torp-Pedersen</p><p>C, Gislason GH, Shaw RE, Hlatky MA. Functional testing or coronary computed</p><p>tomography angiography in patients with stable coronary artery disease. J Am</p><p>Coll Cardiol 2017;69:1761�1770.</p><p>82. Roifman I, Wijeysundera HC, Austin PC, Rezai MR, Wright GA, Tu JV.</p><p>Comparison of anatomic and clinical outcomes in patients undergoing alternative</p><p>initial noninvasive testing strategies for the diagnosis of stable coronary artery</p><p>disease. J Am Heart Assoc 2017;6:e005462.</p><p>83. Shaw LJ, Mieres JH, Hendel RH, Boden WE, Gulati M, Veledar E, Hachamovitch</p><p>R, Arrighi JA, Merz CN, Gibbons RJ, Wenger NK, Heller GV; WOMEN Trial</p><p>Investigators. Comparative effectiveness of exercise electrocardiography with or</p><p>without myocardial perfusion single photon emission computed tomography in</p><p>women with suspected coronary artery disease: results from the What Is the</p><p>Optimal Method for Ischemia Evaluation in Women (WOMEN) trial. Circulation</p><p>2011;124:1239�1249.</p><p>84. Steurer J, Fischer JE, Bachmann LM, Koller M, ter Riet G. Communicating accu-</p><p>racy of tests to general practitioners: a controlled study. BMJ</p><p>2002;324:824�826.</p><p>85. Gueret P, Deux JF, Bonello L, Sarran A, Tron C, Christiaens L, Dacher JN,</p><p>Bertrand D, Leborgne L, Renard C, Caussin C, Cluzel P, Helft G, Crochet D,</p><p>Vernhet-Kovacsik H, Chabbert V, Ferrari E, Gilard M, Willoteaux S, Furber A,</p><p>Barone-Rochette G, Jankowski A, Douek P, Mousseaux E, Sirol M, Niarra R,</p><p>Chatellier G, Laissy JP. Diagnostic performance of computed tomography coro-</p><p>nary angiography (from the prospective national multicenter multivendor</p><p>EVASCAN study). Am J Cardiol 2013;111:471�478.</p><p>86. Karthikeyan G, Guzic Salobir B, Jug B, Devasenapathy N, Alexanderson E, Vitola</p><p>J, Kraft O, Ozkan E, Sharma S, Purohit G, Dolenc Novak M, Meave A, Trevethan</p><p>S, Cerci R, Zier S, Gotthardtova L, Jonszta T, Altin T, Soydal C, Patel C, Gulati</p><p>G, Paez D, Dondi M, Kashyap R. Functional compared to anatomical imaging in</p><p>the initial evaluation of patients with suspected coronary artery disease: an inter-</p><p>national, multi-center, randomized controlled trial (IAEA-SPECT/CTA study).</p><p>J Nucl Cardiol 2017;24:507�517.</p><p>87. Knuuti J, Bengel F, Bax JJ, Kaufmann PA, Le Guludec D, Perrone Filardi P,</p><p>Marcassa C, Ajmone Marsan N, Achenbach S, Kitsiou A, Flotats A, Eeckhout E,</p><p>Minn H, Hesse B. Risks and benefits of cardiac imaging: an analysis of risks related</p><p>to imaging for coronary artery disease. Eur Heart J 2014;35:633�638.</p><p>88. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U,</p><p>Byrne RA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD,</p><p>Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S,</p><p>Yadav R, Zembala MO. 2018 ESC/EACTS Guidelines on myocardial revasculari-</p><p>zation. Eur Heart J 2019;40:87�165.</p><p>89. Escaned J, Echavarria-Pinto M, Garcia-Garcia HM, van de Hoef TP, de Vries T,</p><p>Kaul P, Raveendran G, Altman JD, Kurz HI, Brechtken J, Tulli M, Von Birgelen C,</p><p>Schneider JE, Khashaba AA, Jeremias A, Baucum J, Moreno R, Meuwissen M,</p><p>Mishkel G, van Geuns RJ, Levite H, Lopez-Palop R, Mayhew M, Serruys PW,</p><p>Samady H, Piek JJ, Lerman A; ADVISE II Study Group. Prospective assessment of</p><p>the diagnostic accuracy of instantaneous wave-free ratio to assess coronary</p><p>stenosis relevance: results of ADVISE II international, multicenter study</p><p>(ADenosine Vasodilator Independent Stenosis Evaluation II). JACC Cardiovasc</p><p>Interv 2015;8:824�833.</p><p>90. Toth G, Hamilos M, Pyxaras S, Mangiacapra F, Nelis O, De Vroey F, Di Serafino</p><p>L, Muller O, Van Mieghem C, Wyffels E, Heyndrickx GR, Bartunek J,</p><p>Vanderheyden M, Barbato E, Wijns W, De Bruyne B. Evolving concepts of angio-</p><p>gram: fractional flow reserve discordances in 4000 coronary stenoses. Eur Heart J</p><p>2014;35:2831�2838.</p><p>91. Jeremias A, Maehara A, Genereux P, Asrress KN, Berry C, De Bruyne B, Davies</p><p>JE, Escaned J, Fearon WF, Gould KL, Johnson NP, Kirtane AJ, Koo BK, Marques</p><p>KM, Nijjer S, Oldroyd KG, Petraco R, Piek JJ, Pijls NH, Redwood S, Siebes M,</p><p>Spaan JAE, van ’t Veer M, Mintz GS, Stone GW. Multicenter core laboratory</p><p>comparison of the instantaneous wave-free ratio and resting Pd/Pa with frac-</p><p>tional flow reserve: the RESOLVE study. J Am Coll Cardiol 2014;63:1253�1261.</p><p>92. Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, Champagne S,</p><p>Belle L, Barreau D, Hanssen M, Besnard C, Dauphin R, Dallongeville J, El Hahi Y,</p><p>Sideris G, Bretelle C, Lhoest N, Barnay P, Leborgne L, Dupouy P; Investigators of</p><p>the Registre Français de la FFR�R3F. Outcome impact of coronary revasculariza-</p><p>tion strategy reclassification with fractional flow reserve at time of diagnostic</p><p>angiography: insights from a large French multicenter fractional flow reserve</p><p>registry. Circulation 2014;129:173�185.</p><p>93. Curzen N, Rana O, Nicholas Z, Golledge P, Zaman A, Oldroyd K, Hanratty C,</p><p>Banning A, Wheatcroft S, Hobson A, Chitkara K, Hildick-Smith D, McKenzie D,</p><p>Calver A, Dimitrov BD, Corbett S. Does routine pressure wire assessment influ-</p><p>ence management strategy at coronary angiography for diagnosis of chest pain?:</p><p>the RIPCORD study. Circ Cardiovasc Interv 2014;7:248�255.</p><p>94. Mason PJ, Shah B, Tamis-Holland JE, Bittl JA, Cohen MG, Safirstein J, Drachman</p><p>DE, Valle JA, Rhodes D, Gilchrist IC; American Heart Association Interventional</p><p>Cardiovascular Care Committee of the Council on Clinical Cardiology; Council</p><p>on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease;</p><p>Council on Genomic and Precision Medicine. An update on radial artery access</p><p>and best practices for transradial coronary angiography and intervention in acute</p><p>coronary syndrome: a scientific statement from the American Heart Association.</p><p>Circ Cardiovasc Interv 2018;11:e000035.</p><p>95. Arora N, Matheny ME, Sepke C, Resnic FS. A propensity analysis of the risk of</p><p>vascular complications after cardiac catheterization procedures with the use of</p><p>vascular closure devices. Am Heart J 2007;153:606�611.</p><p>96. Noto TJ Jr, Johnson LW, Krone R, Weaver WF, Clark DA, Kramer JR Jr,</p><p>Vetrovec GW. Cardiac catheterization 1990: a report of the Registry of the</p><p>Society for Cardiac Angiography and Interventions (SCA&I). Cathet Cardiovasc</p><p>Diagn 1991;24:75�83.</p><p>97. Abidov A, Rozanski A, Hachamovitch R, Hayes SW, Aboul-Enein F, Cohen I,</p><p>Friedman JD, Germano G, Berman DS. Prognostic significance of</p><p>dyspnea in patients referred for cardiac stress testing. N Engl J Med</p><p>2005;353:1889�1898.</p><p>98. Gupta S, Rohatgi A, Ayers CR, Willis BL, Haskell WL, Khera A, Drazner MH, de</p><p>Lemos JA, Berry JD. Cardiorespiratory fitness and classification of risk of cardio-</p><p>vascular disease mortality. Circulation 2011;123:1377�1383.</p><p>99. Gulati M, Black HR, Shaw LJ, Arnsdorf MF, Merz CN, Lauer MS, Marwick TH,</p><p>Pandey DK, Wicklund RH, Thisted RA. The prognostic value of a nomogram for</p><p>exercise capacity in women. N Engl J Med 2005;353:468�475.</p><p>100. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise</p><p>capacity and mortality among men referred for exercise testing. N Engl J Med</p><p>2002;346:793�801.</p><p>101. Emond M, Mock MB, Davis KB, Fisher LD, Holmes DR Jr, Chaitman BR, Kaiser</p><p>GC, Alderman E, Killip T III. Long-term survival of medically treated patients in</p><p>the Coronary Artery Surgery Study (CASS) Registry. Circulation</p><p>1994;90:2645�2657.</p><p>102. Mark DB, Shaw L, Harrell FE Jr, Hlatky MA, Lee KL, Bengtson JR, McCants CB,</p><p>Califf RM, Pryor DB. Prognostic value of a treadmill exercise score in</p><p>outpatients with suspected coronary artery disease. N Engl J Med</p><p>1991;325:849�853.</p><p>103. Shaw LJ, Berman DS, Picard MH, Friedrich MG, Kwong RY, Stone GW, Senior</p><p>R, Min JK, Hachamovitch R, Scherrer-Crosbie M, Mieres JH, Marwick TH,</p><p>Phillips LM, Chaudhry FA, Pellikka PA, Slomka P, Arai AE, Iskandrian AE,</p><p>Bateman TM, Heller GV, Miller TD, Nagel E, Goyal A, Borges-Neto S, Boden</p><p>WE, Reynolds HR, Hochman JS, Maron DJ, Douglas PS; National Institutes of</p><p>Health/National Heart, Lung, and Blood Institute-Sponsored ISCHEMIA Trial</p><p>Investigators. Comparative definitions for moderate-severe ischemia in stress</p><p>nuclear, echocardiography, and magnetic resonance imaging. JACC Cardiovasc</p><p>Imaging 2014;7:593�604.</p><p>104. Johnson NP, Toth GG, Lai D, Zhu H, Acar G, Agostoni P, Appelman Y, Arslan</p><p>F, Barbato E, Chen SL, Di Serafino L, Dominguez-Franco AJ, Dupouy P, Esen</p><p>AM, Esen OB, Hamilos M, Iwasaki K, Jensen LO, Jimenez-Navarro MF, Katritsis</p><p>DG, Kocaman SA, Koo BK, Lopez-Palop R, Lorin JD, Miller LH, Muller O, Nam</p><p>CW, Oud N, Puymirat E, Rieber J, Rioufol G, Rodes-Cabau J, Sedlis SP, Takeishi</p><p>Y, Tonino PA, Van Belle E, Verna E, Werner GS, Fearon WF, Pijls NH, De</p><p>Bruyne B, Gould KL. Prognostic value of fractional flow reserve: linking physio-</p><p>logic severity to clinical outcomes. J Am Coll Cardiol 2014;64:1641�1654.</p><p>105. Smulders MW, Jaarsma C, Nelemans PJ, Bekkers S, Bucerius J, Leiner T, Crijns</p><p>H, Wildberger JE, Schalla S. Comparison of the prognostic value of negative</p><p>non-invasive cardiac investigations in patients with suspected or known coro-</p><p>nary artery disease-a meta-analysis. Eur Heart J Cardiovasc Imaging</p><p>2017;18:980�987.</p><p>106. Hachamovitch R, Rozanski A, Shaw LJ, Stone GW, Thomson LE, Friedman JD,</p><p>Hayes SW, Cohen I, Germano G, Berman DS. Impact of ischaemia and scar on</p><p>the therapeutic benefit derived from myocardial revascularization vs. medical</p><p>therapy among patients undergoing stress-rest myocardial perfusion scintigra-</p><p>phy. Eur Heart J 2011;32:1012�1024.</p><p>107. Barbato E, Toth GG, Johnson NP, Pijls NH, Fearon WF, Tonino PA, Curzen N,</p><p>Piroth Z, Rioufol G, Juni P, De Bruyne B. A prospective natural history study of</p><p>coronary atherosclerosis using fractional flow reserve. J Am Coll Cardiol</p><p>2016;68:2247�2255.</p><p>108. Maaniitty T, Stenstrom I, Bax JJ, Uusitalo V, Ukkonen H, Kajander S, Maki M,</p><p>Saraste A, Knuuti J. Prognostic value of coronary CT angiography with selective</p><p>PET perfusion imaging in coronary artery disease. JACC Cardiovasc Imaging</p><p>2017;10:1361�1370.</p><p>464 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>109. Pazhenkottil AP, Nkoulou RN, Ghadri JR, Herzog BA, Buechel RR, Kuest SM,</p><p>Wolfrum M, Fiechter M, Husmann L, Gaemperli O, Kaufmann PA. Prognostic</p><p>value of cardiac hybrid imaging integrating single-photon emission computed</p><p>tomography with coronary computed tomography angiography. Eur Heart J</p><p>2011;32:1465�1471.</p><p>110. Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from global</p><p>longitudinal speckle strain: comparison with ejection fraction and wall motion</p><p>scoring. Circ Cardiovasc Imaging 2009;2:356�364.</p><p>111. Haugaa KH, Grenne BL, Eek CH, Ersboll M, Valeur N, Svendsen JH, Florian A,</p><p>Sjoli B, Brunvand H, Kober L, Voigt JU, Desmet W, Smiseth OA, Edvardsen T.</p><p>Strain echocardiography improves risk prediction of ventricular arrhythmias</p><p>after myocardial infarction. JACC Cardiovasc Imaging 2013;6:841�850.</p><p>112. Ng ACT, Prihadi EA, Antoni ML, Bertini M, Ewe SH, Ajmone Marsan N, Leung</p><p>DY, Delgado V, Bax JJ. Left ventricular global longitudinal strain is predictive of</p><p>all-cause mortality independent of aortic stenosis severity and ejection fraction.</p><p>Eur Heart J Cardiovasc Imaging 2018;19:859�867.</p><p>113. Kalam K, Otahal P, Marwick TH. Prognostic implications of global LV dysfunc-</p><p>tion: a systematic review and meta-analysis of global longitudinal strain and ejec-</p><p>tion fraction. Heart 2014;100:1673�1680.</p><p>114. Scharrenbroich J, Hamada S, Keszei A, Schroder J, Napp A, Almalla M, Becker</p><p>M, Altiok E. Use of two-dimensional speckle tracking echocardiography to pre-</p><p>dict cardiac events: comparison of patients with acute myocardial infarction and</p><p>chronic coronary artery disease. Clin Cardiol 2018;41:111�118.</p><p>115. Park SJ, Ahn JM, Kang SJ, Yoon SH, Koo BK, Lee JY, Kim WJ, Park DW, Lee</p><p>SW, Kim YH, Lee CW, Park SW. Intravascular ultrasound-derived minimal</p><p>lumen area criteria for functionally significant left main coronary artery stenosis.</p><p>JACC Cardiovasc Interv 2014;7:868�874.</p><p>116. D’Ascenzo F, Barbero U, Cerrato E, Lipinski MJ, Omede P, Montefusco A, Taha</p><p>S, Naganuma T, Reith S, Voros S, Latib A, Gonzalo N, Quadri G, Colombo A,</p><p>Biondi-Zoccai G, Escaned J, Moretti C, Gaita F. Accuracy of intravascular ultra-</p><p>sound and optical coherence tomography in identifying functionally significant</p><p>coronary stenosis according to vessel diameter: a meta-analysis of 2,581</p><p>patients and 2,807 lesions. Am Heart J 2015;169:663�673.</p><p>117. Maron DJ, Boden WE, O’Rourke RA, Hartigan PM, Calfas KJ, Mancini GB,</p><p>Spertus JA, Dada M, Kostuk WJ, Knudtson M, Harris CL, Sedlis SP, Zoble RG,</p><p>Title LM, Gosselin G, Nawaz S, Gau GT, Blaustein AS, Bates ER, Shaw LJ,</p><p>Berman DS, Chaitman BR, Weintraub WS, Teo KK; COURAGE Trial Research</p><p>Group. Intensive multifactorial intervention for stable coronary artery disease:</p><p>optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing</p><p>Revascularization and Aggressive Drug Evaluation) trial. J Am Coll Cardiol</p><p>2010;55:1348�1358.</p><p>118. Rotenstein LS, Huckman RS, Wagle NW. Making patients and doctors happier -</p><p>the potential of patient-reported outcomes. N Engl J Med</p><p>2017;377:1309�1312.</p><p>119. Chow CK, Jolly S, Rao-Melacini P, Fox KA, Anand SS, Yusuf S. Association of</p><p>diet, exercise, and smoking modification with risk of early cardiovascular events</p><p>after acute coronary syndromes. Circulation 2010;121:750�758.</p><p>120. Booth JN III, Levitan EB, Brown TM, Farkouh ME, Safford MM, Muntner P.</p><p>Effect of sustaining lifestyle modifications (nonsmoking, weight reduction, physi-</p><p>cal activity, and mediterranean diet) after healing of myocardial infarction, per-</p><p>cutaneous intervention, or coronary bypass (from the REasons for Geographic</p><p>and Racial Differences in Stroke Study). Am J Cardiol 2014;113:1933�1940.</p><p>121. Giannuzzi P, Temporelli PL, Marchioli R, Maggioni AP, Balestroni G, Ceci V,</p><p>Chieffo C, Gattone M, Griffo R, Schweiger C, Tavazzi L, Urbinati S, Valagussa F,</p><p>Vanuzzo D; GOSPEL Investigators. Global secondary prevention strategies to</p><p>limit event recurrence after myocardial infarction: results of the GOSPEL study,</p><p>a multicenter, randomized controlled trial from the Italian Cardiac</p><p>Rehabilitation Network. Arch Intern Med 2008;168:2194�2204.</p><p>122. Keteyian SJ, Brawner CA, Savage PD, Ehrman JK, Schairer J, Divine G, Aldred H,</p><p>Ophaug K, Ades PA. Peak aerobic capacity predicts prognosis in patients with</p><p>coronary heart disease. Am Heart J 2008;156:292�300.</p><p>123. Wood DA, Kotseva K, Connolly S, Jennings C, Mead A, Jones J, Holden A, De</p><p>Bacquer D, Collier T, De Backer G, Faergeman O; EUROACTION Study</p><p>Group. Nurse-coordinated multidisciplinary, family-based cardiovascular disease</p><p>prevention programme (EUROACTION) for patients with coronary heart dis-</p><p>ease and asymptomatic individuals at high risk of cardiovascular disease: a</p><p>paired, cluster-randomised controlled trial. Lancet 2008;371:1999�2012.</p><p>124. Critchley JA, Capewell S. Mortality risk reduction associated with smoking ces-</p><p>sation in patients with coronary heart disease: a systematic review. JAMA</p><p>2003;290:86�97.</p><p>125. Prochaska JJ, Benowitz NL. The past, present, and future of nicotine addiction</p><p>therapy. Annu Rev Med 2016;67:467�486.</p><p>126. Barth J, Jacob T, Daha I, Critchley JA. Psychosocial interventions for smoking</p><p>cessation in patients with coronary heart disease. Cochrane Database Syst Rev</p><p>2015;7:CD006886.</p><p>127. Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associ-</p><p>ated with smoking cessation pharmacotherapies: a network meta-analysis.</p><p>Circulation 2014;129:28�41.</p><p>128. Qasim H, Karim ZA, Rivera JO, Khasawneh FT, Alshbool FZ. Impact of elec-</p><p>tronic cigarettes on the cardiovascular system. J Am Heart Assoc</p><p>2017;6:e006353.</p><p>129. El Dib R, Suzumura EA, Akl EA, Gomaa H, Agarwal A, Chang Y, Prasad M,</p><p>Ashoorion V, Heels-Ansdell D, Maziak W, Guyatt G. Electronic nicotine deliv-</p><p>ery systems and/or electronic non-nicotine delivery systems for tobacco smok-</p><p>ing cessation or reduction: a systematic review and meta-analysis. BMJ Open</p><p>2017;7:e012680.</p><p>130. Hartmann-Boyce J, McRobbie H, Bullen C, Begh R, Stead LF, Hajek P. Electronic</p><p>cigarettes for smoking cessation. Cochrane Database Syst Rev 2016;9:CD010216.</p><p>131. Kalkhoran S, Glantz SA. E-cigarettes and smoking cessation in real-world and</p><p>clinical settings: a systematic review and meta-analysis. Lancet Respir Med</p><p>2016;4:116�128.</p><p>132. Malas M, van der Tempel J, Schwartz R, Minichiello A, Lightfoot C,</p><p>Noormohamed A, Andrews J, Zawertailo L, Ferrence R. Electronic cigarettes</p><p>for smoking cessation: a systematic review. Nicotine Tob Res</p><p>2016;18:1926�1936.</p><p>133. Hajek P, Phillips-Waller A, Przulj D, Pesola F, Myers Smith K, Bisal N, Li J,</p><p>Parrott S, Sasieni P, Dawkins L, Ross L, Goniewicz M, Wu Q, McRobbie HJ. A</p><p>randomized trial of E-cigarettes versus nicotine-replacement therapy. N Engl J</p><p>Med 2019;380:629�637.</p><p>134. Freeman AM, Morris PB, Barnard N, Esselstyn CB, Ros E, Agatston A, Devries</p><p>S, O’Keefe J, Miller M, Ornish D, Williams K, Kris-Etherton P. Trending cardio-</p><p>vascular nutrition controversies. J Am Coll Cardiol 2017;69:1172�1187.</p><p>135. Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, Hu FB. Fruit and vegetable</p><p>consumption and mortality from all causes, cardiovascular disease, and cancer:</p><p>systematic review and dose-response meta-analysis of prospective cohort stud-</p><p>ies. BMJ 2014;349:g4490.</p><p>136. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adher-</p><p>ence to the Mediterranean diet on health: an updated systematic review and</p><p>meta-analysis. Am J Clin Nutr 2010;92:1189�1196.</p><p>137. Miller V, Mente A, Dehghan M, Rangarajan S, Zhang X, Swaminathan S,</p><p>Dagenais G, Gupta R, Mohan V, Lear S, Bangdiwala SI, Schutte AE, Wentzel-</p><p>Viljoen E, Avezum A, Altuntas Y, Yusoff K, Ismail N, Peer N, Chifamba J, Diaz R,</p><p>Rahman O, Mohammadifard N, Lana F, Zatonska K, Wielgosz A, Yusufali A,</p><p>Iqbal R, Lopez-Jaramillo P, Khatib R, Rosengren A, Kutty VR, Li W, Liu J, Liu X,</p><p>Yin L, Teo K, Anand S, Yusuf S; Prospective Urban Rural Epidemiology (PURE)</p><p>study investigators. Fruit, vegetable, and legume intake, and cardiovascular dis-</p><p>ease and deaths in 18 countries (PURE): a prospective cohort study. Lancet</p><p>2017;390:2037�2049.</p><p>138. Estruch R, Ros E, Salas-Salvad�o J, Covas MI, Corella D, Ar�os F, G�omez-Gracia</p><p>E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L,</p><p>Pint�o X, Basora J, Mu~noz MA, Sorl�ı JV, Mart�ınez JA, Fit�o M, Gea A, Hern�an MA,</p><p>Mart�ınez-Gonz�alez MA; PREDIMED Study Investigators. Primary prevention of</p><p>cardiovascular disease with a Mediterranean diet supplemented with extra-</p><p>virgin olive oil or nuts. N Engl J Med 2018;378:e34.</p><p>139. Wood AM, Kaptoge S, Butterworth AS, Willeit P, Warnakula S, Bolton T, Paige</p><p>E, Paul DS, Sweeting M, Burgess S, Bell S, Astle W, Stevens D, Koulman A,</p><p>Selmer RM, Verschuren WMM, Sato S, Njolstad I, Woodward M, Salomaa V,</p><p>Nordestgaard BG, Yeap BB, Fletcher A, Melander O, Kuller LH, Balkau B,</p><p>Marmot M, Koenig W, Casiglia E, Cooper C, Arndt V, Franco OH, Wennberg</p><p>P, Gallacher J, de la Camara AG, Volzke H, Dahm CC, Dale CE, Bergmann MM,</p><p>Crespo CJ, van der Schouw YT, Kaaks R, Simons LA, Lagiou P, Schoufour JD,</p><p>Boer JMA, Key TJ, Rodriguez B, Moreno-Iribas C, Davidson KW, Taylor JO,</p><p>Sacerdote C, Wallace RB, Quiros JR, Tumino R, Blazer DG II, Linneberg A,</p><p>Daimon M, Panico S, Howard B, Skeie G, Strandberg T, Weiderpass E, Nietert</p><p>PJ, Psaty BM, Kromhout D, Salamanca-Fernandez E, Kiechl S, Krumholz HM,</p><p>Grioni S, Palli D, Huerta JM, Price J, Sundstrom J, Arriola L, Arima H, Travis RC,</p><p>Panagiotakos DB, Karakatsani A, Trichopoulou A, Kuhn T, Grobbee DE,</p><p>Barrett-Connor E, van Schoor N, Boeing H, Overvad K, Kauhanen J, Wareham</p><p>N, Langenberg C, Forouhi N, Wennberg M, Despres JP, Cushman M, Cooper</p><p>JA, Rodriguez CJ, Sakurai M, Shaw JE, Knuiman M, Voortman T, Meisinger C,</p><p>Tjonneland A, Brenner H, Palmieri L, Dallongeville J, Brunner EJ, Assmann G,</p><p>Trevisan M, Gillum RF, Ford I, Sattar N, Lazo M, Thompson SG, Ferrari P, Leon</p><p>DA, Smith GD, Peto R, Jackson R, Banks E, Di Angelantonio E, Danesh J;</p><p>Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study</p><p>Group. Risk thresholds for alcohol consumption: combined analysis of</p><p>individual-participant data for 599 912 current drinkers in 83 prospective stud-</p><p>ies. Lancet 2018;391:1513�1523.</p><p>140. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries</p><p>and territories, 1990-2016: a systematic analysis for the Global Burden of</p><p>Disease</p><p>Study 2016. Lancet 2018;392:1015�1035.</p><p>ESC Guidelines 465</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>141. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj</p><p>A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of</p><p>potentially modifiable risk factors associated with myocardial infarction in 52</p><p>countries (the INTERHEART study): case-control study. Lancet</p><p>2004;364:937�952.</p><p>142. Piano MR. Alcohol’s effects on the cardiovascular system. Alcohol Res</p><p>2017;38:219�241.</p><p>143. Khan SS, Ning H, Wilkins JT, Allen N, Carnethon M, Berry JD, Sweis RN, Lloyd-</p><p>Jones DM. Association of body mass index with lifetime risk of cardiovascular</p><p>disease and compression of morbidity. JAMA Cardiol 2018;3:280�287.</p><p>144. Pack QR, Rodriguez-Escudero JP, Thomas RJ, Ades PA, West CP, Somers VK,</p><p>Lopez-Jimenez F. The prognostic importance of weight loss in coronary artery</p><p>disease: a systematic review and meta-analysis. Mayo Clin Proc</p><p>2014;89:1368�1377.</p><p>145. Gardner CD, Trepanowski JF, Del Gobbo LC, Hauser ME, Rigdon J, Ioannidis</p><p>JPA, Desai M, King AC. Effect of low-fat vs low-carbohydrate diet on 12-month</p><p>weight loss in overweight adults and the association with genotype pattern or</p><p>insulin secretion: the DIETFITS randomized clinical trial. JAMA</p><p>2018;319:667�679.</p><p>146. Fiuza-Luces C, Garatachea N, Berger NA, Lucia A. Exercise is the real polypill.</p><p>Physiology (Bethesda) 2013;28:330�358.</p><p>147. Bruning RS, Sturek M. Benefits of exercise training on coronary blood flow in</p><p>coronary artery disease patients. Prog Cardiovasc Dis 2015;57:443�453.</p><p>148. Cheng W, Zhang Z, Cheng W, Yang C, Diao L, Liu W. Associations of leisure-</p><p>time physical activity with cardiovascular mortality: a systematic review and</p><p>meta-analysis of 44 prospective cohort studies. Eur J Prev Cardiol</p><p>2018;25:1864�1872.</p><p>149. Lahtinen M, Toukola T, Junttila MJ, Piira OP, Lepojarvi S, Kaariainen M, Huikuri HV,</p><p>Tulppo MP, Kiviniemi AM. Effect of changes in physical activity on risk for cardiac</p><p>death in patients with coronary artery disease. Am J Cardiol 2018;121:143�148.</p><p>150. Stewart RAH, Held C, Hadziosmanovic N, Armstrong PW, Cannon CP,</p><p>Granger CB, Hagstrom E, Hochman JS, Koenig W, Lonn E, Nicolau JC, Steg PG,</p><p>Vedin O, Wallentin L, White HD; STABILITY Investigators. Physical activity and</p><p>mortality in patients with stable coronary heart disease. J Am Coll Cardiol</p><p>2017;70:1689�1700.</p><p>151. Anderson L, Thompson DR, Oldridge N, Zwisler AD, Rees K, Martin N, Taylor</p><p>RS. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane</p><p>Database Syst Rev 2016;1:CD001800.</p><p>152. Rauch B, Davos CH, Doherty P, Saure D, Metzendorf MI, Salzwedel A, Voller</p><p>H, Jensen K, Schmid JP; ‘Cardiac Rehabilitation Section’, European Association</p><p>of Preventive Cardiology (EAPC), in cooperation with the Institute of Medical</p><p>Biometry and Informatics (IMBI), Department of Medical Biometry, University</p><p>of Heidelberg, Cochrane Metabolic and Endocrine Disorders Group, Institute</p><p>of General Practice, Heinrich-Heine University, Düsseldorf, Germany. The</p><p>prognostic effect of cardiac rehabilitation in the era of acute revascularisation</p><p>and statin therapy: A systematic review and meta-analysis of randomized and</p><p>non-randomized studies - The Cardiac Rehabilitation Outcome Study (CROS).</p><p>Eur J Prev Cardiol 2016;23:1914�1939.</p><p>153. de Vries H, Kemps HM, van Engen-Verheul MM, Kraaijenhagen RA, Peek N.</p><p>Cardiac rehabilitation and survival in a large representative community cohort</p><p>of Dutch patients. Eur Heart J 2015;36:1519�1528.</p><p>154. Benzer W, Rauch B, Schmid JP, Zwisler AD, Dendale P, Davos CH, Kouidi E,</p><p>Simon A, Abreu A, Pogosova N, Gaita D, Miletic B, Bonner G, Ouarrak T,</p><p>McGee H; EuroCaReD study group. Exercise-based cardiac rehabilitation in</p><p>twelve European countries results of the European cardiac rehabilitation regis-</p><p>try. Int J Cardiol 2017;228:58�67.</p><p>155. Ormel J, Von Korff M, Burger H, Scott K, Demyttenaere K, Huang YQ, Posada-</p><p>Villa J, Pierre Lepine J, Angermeyer MC, Levinson D, de Girolamo G, Kawakami</p><p>N, Karam E, Medina-Mora ME, Gureje O, Williams D, Haro JM, Bromet EJ,</p><p>Alonso J, Kessler R. Mental disorders among persons with heart disease -</p><p>results from World Mental Health surveys. Gen Hosp Psychiatry</p><p>2007;29:325�334.</p><p>156. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease</p><p>and depression. Biol Psychiatry 2003;54:227�240.</p><p>157. Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interven-</p><p>tions for depression in patients with coronary artery disease. Cochrane Database</p><p>Syst Rev 2011;9:CD008012.</p><p>158. Richards SH, Anderson L, Jenkinson CE, Whalley B, Rees K, Davies P, Bennett</p><p>P, Liu Z, West R, Thompson DR, Taylor RS. Psychological interventions for</p><p>coronary heart disease: Cochrane systematic review and meta-analysis. Eur J</p><p>Prev Cardiol 2018;25:247�259.</p><p>159. Rutledge T, Redwine LS, Linke SE, Mills PJ. A meta-analysis of mental health treat-</p><p>ments and cardiac rehabilitation for improving clinical outcomes and depression</p><p>among patients with coronary heart disease. Psychosom Med 2013;75:335�349.</p><p>160. Brook RD, Newby DE, Rajagopalan S. Air pollution and cardiometabolic dis-</p><p>ease: an update and call for clinical trials. Am J Hypertens 2017;31:1�10.</p><p>161. Munzel T, Schmidt FP, Steven S, Herzog J, Daiber A, Sorensen M.</p><p>Environmental noise and the cardiovascular system. J Am Coll Cardiol</p><p>2018;71:688�697.</p><p>162. Steinke EE, Jaarsma T, Barnason SA, Byrne M, Doherty S, Dougherty CM,</p><p>Fridlund B, Kautz DD, Martensson J, Mosack V, Moser DK; Council on</p><p>Cardiovascular and Stroke Nursing of the American Heart Association and the</p><p>ESC Council on Cardiovascular Nursing and Allied Professions (CCNAP).</p><p>Sexual counselling for individuals with cardiovascular disease and their partners:</p><p>a consensus document from the American Heart Association and the ESC</p><p>Council on Cardiovascular Nursing and Allied Professions (CCNAP). Eur Heart</p><p>J 2013;34:3217�3235.</p><p>163. Bispo GS, de Lima Lopes J, de Barros AL. Cardiovascular changes resulting</p><p>from sexual activity and sexual dysfunction after myocardial infarction: integra-</p><p>tive review. J Clin Nurs 2013;22:3522�3531.</p><p>164. Levine GN, Steinke EE, Bakaeen FG, Bozkurt B, Cheitlin MD, Conti JB, Foster E,</p><p>Jaarsma T, Kloner RA, Lange RA, Lindau ST, Maron BJ, Moser DK, Ohman EM,</p><p>Seftel AD, Stewart WJ; American Heart Association Council on Clinical</p><p>Cardiology; Council on Cardiovascular Nursing; Council on Cardiovascular</p><p>Surgery and Anesthesia; Council on Quality of Care and Outcomes Research.</p><p>Sexual activity and cardiovascular disease: a scientific statement from the</p><p>American Heart Association. Circulation 2012;125:1058�1072.</p><p>165. Stein R, Sardinha A, Araujo CG. Sexual activity and heart patients: a contempo-</p><p>rary perspective. Can J Cardiol 2016;32:410�420.</p><p>166. Steinke EE, Mosack V, Hill TJ. Change in sexual activity after a cardiac event: the</p><p>role of medications, comorbidity, and psychosocial factors. Appl Nurs Res</p><p>2015;28:244�250.</p><p>167. Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B,</p><p>Mendis S, Hofman A, Mant J, Franco OH. Adherence to cardiovascular therapy:</p><p>a meta-analysis of prevalence and clinical consequences. Eur Heart J</p><p>2013;34:2940�2948.</p><p>168. Gnjidic D, Bennett A, Le Couteur DG, Blyth FM, Cumming RG, Waite L,</p><p>Handelsman D, Naganathan V, Matthews S, Hilmer SN. Ischemic heart disease,</p><p>prescription of optimal medical therapy and geriatric syndromes in community-</p><p>dwelling older men: a population-based study. Int J Cardiol 2015;192:49�55.</p><p>169. Mohammed S, Arabi A, El-Menyar A, Abdulkarim S, AlJundi A, Alqahtani A,</p><p>Arafa S, Al Suwaidi J. Impact of polypharmacy on adherence to</p><p>evidence-based</p><p>medication in patients who underwent percutaneous coronary intervention.</p><p>Curr Vasc Pharmacol 2016;14:388�393.</p><p>170. Wimmer BC, Cross AJ, Jokanovic N, Wiese MD, George J, Johnell K, Diug B,</p><p>Bell JS. Clinical outcomes associated with medication regimen complexity in</p><p>older people: a systematic review. J Am Geriatr Soc 2017;65:747�753.</p><p>171. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A,</p><p>Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA,</p><p>Jedraszewski D, Cotoi C, Haynes RB. Interventions for enhancing medication</p><p>adherence. Cochrane Database Syst Rev 2014;11:CD000011.</p><p>172. Demonceau J, Ruppar T, Kristanto P, Hughes DA, Fargher E, Kardas P, De</p><p>Geest S, Dobbels F, Lewek P, Urquhart J, Vrijens B; ABC project team.</p><p>Identification and assessment of adherence-enhancing interventions in studies</p><p>assessing medication adherence through electronically compiled drug dosing</p><p>histories: a systematic literature review and meta-analysis. Drugs</p><p>2013;73:545�562.</p><p>173. Acharjee S, Teo KK, Jacobs AK, Hartigan PM, Barn K, Gosselin G, Tanguay JF,</p><p>Maron DJ, Kostuk WJ, Chaitman BR, Mancini GB, Spertus JA, Dada MR, Bates</p><p>ER, Booth DC, Weintraub WS, O’Rourke RA, Boden WE; COURAGE Trial</p><p>Research Group. Optimal medical therapy with or without percutaneous coro-</p><p>nary intervention in women with stable coronary disease: a pre-specified subset</p><p>analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive</p><p>druG Evaluation (COURAGE) trial. Am Heart J 2016;173:108�117.</p><p>174. Koertge J, Weidner G, Elliott-Eller M, Scherwitz L, Merritt-Worden TA, Marlin</p><p>R, Lipsenthal L, Guarneri M, Finkel R, Saunders DE Jr, McCormac P, Scheer JM,</p><p>Collins RE, Ornish D. Improvement in medical risk factors and quality of life in</p><p>women and men with coronary artery disease in the Multicenter Lifestyle</p><p>Demonstration Project. Am J Cardiol 2003;91:1316�1322.</p><p>175. MacIntyre CR, Mahimbo A, Moa AM, Barnes M. Influenza vaccine as a coronary</p><p>intervention for prevention of myocardial infarction. Heart</p><p>2016;102:1953�1956.</p><p>176. Hebsur S, Vakil E, Oetgen WJ, Kumar PN, Lazarous DF. Influenza and coronary</p><p>artery disease: exploring a clinical association with myocardial infarction and</p><p>analyzing the utility of vaccination in prevention of myocardial infarction. Rev</p><p>Cardiovasc Med 2014;15:168�175.</p><p>177. Kadoglou NPE, Bracke F, Simmers T, Tsiodras S, Parissis J. Influenza infection</p><p>and heart failure-vaccination may change heart failure prognosis? Heart Fail Rev</p><p>2017;22:329�336.</p><p>178. Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, Rees K. Influenza vaccines for</p><p>preventing cardiovascular disease. Cochrane Database Syst Rev</p><p>2015;5:CD005050.</p><p>466 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>179. Paules CI, Subbarao K. Influenza vaccination and prevention of cardiovascular</p><p>disease mortality - Authors’ reply. Lancet 2018;391:427�428.</p><p>180. Mohseni H, Kiran A, Khorshidi R, Rahimi K. Influenza vaccination and risk of</p><p>hospitalization in patients with heart failure: a self-controlled case series study.</p><p>Eur Heart J 2017;38:326�333.</p><p>181. Artinian NT, Fletcher GF, Mozaffarian D, Kris-Etherton P, Van Horn L,</p><p>Lichtenstein AH, Kumanyika S, Kraus WE, Fleg JL, Redeker NS, Meininger JC,</p><p>Banks J, Stuart-Shor EM, Fletcher BJ, Miller TD, Hughes S, Braun LT, Kopin LA,</p><p>Berra K, Hayman LL, Ewing LJ, Ades PA, Durstine JL, Houston-Miller N, Burke</p><p>LE; American Heart Association Prevention Committee of the Council on</p><p>Cardiovascular Nursing. Interventions to promote physical activity and dietary</p><p>lifestyle changes for cardiovascular risk factor reduction in adults: a scientific</p><p>statement from the American Heart Association. Circulation</p><p>2010;122:406�441.</p><p>182. Janssen V, De Gucht V, Dusseldorp E, Maes S. Lifestyle modification programmes</p><p>for patients with coronary heart disease: a systematic review and meta-analysis of</p><p>randomized controlled trials. Eur J Prev Cardiol 2013;20:620�640.</p><p>183. Aldcroft SA, Taylor NF, Blackstock FC, O’Halloran PD. Psychoeducational</p><p>rehabilitation for health behavior change in coronary artery disease: a systematic</p><p>review of controlled trials. J Cardiopulm Rehabil Prev 2011;31:273�281.</p><p>184. Voogdt-Pruis HR, Beusmans GH, Gorgels AP, Kester AD, Van Ree JW.</p><p>Effectiveness of nurse-delivered cardiovascular risk management in primary</p><p>care: a randomised trial. Br J Gen Pract 2010;60:40�46.</p><p>185. Caldeira D, Ferreira JJ, Costa J. Influenza vaccination and prevention of cardio-</p><p>vascular disease mortality. Lancet 2018;391:426�427.</p><p>186. Caldeira D, Costa J, Vaz-Carneiro A. [Analysis of the Cochrane Review:</p><p>Influenza Vaccines for Preventing Cardiovascular Disease. Cochrane Database</p><p>Syst Rev. 2015;5:CD005050]. Acta Med Port 2015;28:424�426.</p><p>187. Udell JA, Farkouh ME, Solomon SD, Vardeny O. Does influenza vaccination influence</p><p>cardiovascular complications? Expert Rev Cardiovasc Ther 2015;13:593�596.</p><p>188. Camm AJ, Manolis A, Ambrosio G, Daly C, Komajda M, Lopez de Sa E, Lopez-</p><p>Sendon JL, Mugelli A, Muggli F, Tamargo J. Unresolved issues in the manage-</p><p>ment of chronic stable angina. Int J Cardiol 2015;201:200�207.</p><p>189. Ferrari R, Camici PG, Crea F, Danchin N, Fox K, Maggioni AP, Manolis AJ, Marzilli</p><p>M, Rosano GMC, Lopez-Sendon JL. Expert consensus document: A ‘diamond’</p><p>approach to personalized treatment of angina. Nat Rev Cardiol 2018;15:120�132.</p><p>190. Ambrosio G, Mugelli A, Lopez-Sendon J, Tamargo J, Camm J. Management of</p><p>stable angina: A commentary on the European Society of Cardiology guidelines.</p><p>Eur J Prev Cardiol 2016;23:1401�1412.</p><p>191. Thadani U. Management of stable angina - current guidelines: a critical appraisal.</p><p>Cardiovasc Drugs Ther 2016;30:419�426.</p><p>192. Husted SE, Ohman EM. Pharmacological and emerging therapies in the treat-</p><p>ment of chronic angina. Lancet 2015;386:691�701.</p><p>193. National Institute for Health and Care Excellence (NICE). Stable angina: man-</p><p>agement. Clinical guideline [CG126]. https://www.nice.org.uk/guidance/cg126</p><p>(28 March 2019).</p><p>194. Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with com-</p><p>bined antianginal drugs in the treatment of chronic stable angina pectoris: a</p><p>meta-analysis. Coron Artery Dis 2002;13:427�436.</p><p>195. Rousan TA, Mathew ST, Thadani U. Drug therapy for stable angina pectoris.</p><p>Drugs 2017;77:265�284.</p><p>196. Pehrsson SK, Ringqvist I, Ekdahl S, Karlson BW, Ulvenstam G, Persson S.</p><p>Monotherapy with amlodipine or atenolol versus their combination in stable</p><p>angina pectoris. Clin Cardiol 2000;23:763�770.</p><p>197. Emanuelsson H, Egstrup K, Nikus K, Ellstrom J, Glud T, Pater C, Scheibel M,</p><p>Tisell A, Totterman KJ, Forsby M. Antianginal efficacy of the combination of</p><p>felodipine-metoprolol 10/100 mg compared with each drug alone in patients</p><p>with stable effort-induced angina pectoris: a multicenter parallel group study.</p><p>The TRAFFIC Study Group. Am Heart J 1999;137:854�862.</p><p>198. Belsey J, Savelieva I, Mugelli A, Camm AJ. Relative efficacy of antianginal drugs</p><p>used as add-on therapy in patients with stable angina: a systematic review and</p><p>meta-analysis. Eur J Prev Cardiol 2015;22:837�848.</p><p>199. Wight LJ, VandenBurg MJ, Potter CE, Freeth CJ. A large scale comparative study</p><p>in general practice with nitroglycerin spray and tablet formulations in elderly</p><p>patients with angina pectoris. Eur J Clin Pharmacol 1992;42:341�342.</p><p>200. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, Hlatky</p><p>MA. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and</p><p>nitrates for stable angina. JAMA 1999;281:1927�1936.</p><p>201. Wei J, Wu T, Yang Q, Chen M, Ni J, Huang D. Nitrates for stable angina: a sys-</p><p>tematic review and meta-analysis</p><p>of randomized clinical trials. Int J Cardiol</p><p>2011;146:4�12.</p><p>202. Ferratini M. Risk of rebound phenomenon during nitrate withdrawal. Int J</p><p>Cardiol 1994;45:89�96.</p><p>203. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of</p><p>resting heart rate in patients with suspected or proven coronary artery disease.</p><p>Eur Heart J 2005;26:967�974.</p><p>204. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P.</p><p>Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med</p><p>2005;352:1951�1958.</p><p>205. Shu de F, Dong BR, Lin XF, Wu TX, Liu GJ. Long-term beta blockers for stable</p><p>angina: systematic review and meta-analysis. Eur J Prev Cardiol 2012;19:330�341.</p><p>206. Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ. The Total Ischaemic Burden</p><p>European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination</p><p>on the exercise test and the total ischaemic burden in 608 patients with stable</p><p>angina. The TIBET Study Group. Eur Heart J 1996;17:96�103.</p><p>207. Wallace WA, Wellington KL, Chess MA, Liang CS. Comparison of nifedipine</p><p>gastrointestinal therapeutic system and atenolol on antianginal efficacies and</p><p>exercise hemodynamic responses in stable angina pectoris. Am J Cardiol</p><p>1994;73:23�28.</p><p>208. Kawanishi DT, Reid CL, Morrison EC, Rahimtoola SH. Response of angina and</p><p>ischemia to long-term treatment in patients with chronic stable angina: a</p><p>double-blind randomized individualized dosing trial of nifedipine, propranolol</p><p>and their combination. J Am Coll Cardiol 1992;19:409�417.</p><p>209. Bangalore S, Bhatt DL, Steg PG, Weber MA, Boden WE, Hamm CW,</p><p>Montalescot G, Hsu A, Fox KA, Lincoff AM. beta-blockers and cardiovascular</p><p>events in patients with and without myocardial infarction: post hoc analysis</p><p>from the CHARISMA trial. Circ Cardiovasc Qual Outcomes 2014;7:872�881.</p><p>210. Andersson C, Shilane D, Go AS, Chang TI, Kazi D, Solomon MD, Boothroyd</p><p>DB, Hlatky MA. b-blocker therapy and cardiac events among patients</p><p>with newly diagnosed coronary heart disease. J Am Coll Cardiol 2014;64:</p><p>247�252.</p><p>211. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda</p><p>M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A,</p><p>Skene A; Carvedilol Or Metoprolol European Trial Investigators. Comparison</p><p>of carvedilol and metoprolol on clinical outcomes in patients with chronic heart</p><p>failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised</p><p>controlled trial. Lancet 2003;362:7�13.</p><p>212. Leizorovicz A, Lechat P, Cucherat M, Bugnard F. Bisoprolol for the treatment</p><p>of chronic heart failure: a meta-analysis on individual data of two placebo-</p><p>controlled studies–CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study. Am</p><p>Heart J 2002;143:301�307.</p><p>213. Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade after myo-</p><p>cardial infarction: systematic review and meta regression analysis. BMJ</p><p>1999;318:1730�1737.</p><p>214. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM,</p><p>Shusterman NH. The effect of carvedilol on morbidity and mortality in patients</p><p>with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J</p><p>Med 1996;334:1349�1355.</p><p>215. Hwang D, Lee JM, Kim HK, Choi KH, Rhee TM, Park J, Park TK, Yang JH, Song</p><p>YB, Choi JH, Hahn JY, Choi SH, Koo BK, Kim YJ, Chae SC, Cho MC, Kim CJ,</p><p>Gwon HC, Jeong MH, Kim HS; KAMIR Investigators. Prognostic impact of beta-</p><p>blocker dose after acute myocardial infarction. Circ J 2019;83:410�417.</p><p>216. Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, Ruddox V, Munkhaugen J, Atar</p><p>D, Otterstad JE. Effect of oral beta-blocker treatment on mortality in contem-</p><p>porary post-myocardial infarction patients: a systematic review and meta-analy-</p><p>sis. Eur Heart J Cardiovasc Pharmacother 2019;5:12�20.</p><p>217. Bangalore S, Steg G, Deedwania P, Crowley K, Eagle KA, Goto S, Ohman EM,</p><p>Cannon CP, Smith SC, Zeymer U, Hoffman EB, Messerli FH, Bhatt DL; REACH</p><p>Registry Investigators. b-Blocker use and clinical outcomes in stable outpatients</p><p>with and without coronary artery disease. JAMA 2012;308:1340�1349.</p><p>218. Motivala AA, Parikh V, Roe M, Dai D, Abbott JD, Prasad A, Mukherjee D.</p><p>Predictors, trends, and outcomes (among older patients >_65 years of age) asso-</p><p>ciated with beta-blocker use in patients with stable angina undergoing elective</p><p>percutaneous coronary intervention: insights From the NCDR registry. JACC</p><p>Cardiovasc Interv 2016;9:1639�1648.</p><p>219. Zhang H, Yuan X, Zhang H, Chen S, Zhao Y, Hua K, Rao C, Wang W, Sun H,</p><p>Hu S, Zheng Z. Efficacy of long-term beta-blocker therapy for secondary pre-</p><p>vention of long-term outcomes after coronary artery bypass grafting surgery.</p><p>Circulation 2015;131:2194�2201.</p><p>220. Puymirat E, Riant E, Aissaoui N, Soria A, Ducrocq G, Coste P, Cottin Y,</p><p>Aupetit JF, Bonnefoy E, Blanchard D, Cattan S, Steg G, Schiele F, Ferrières J,</p><p>Juillière Y, Simon T, Danchin N. b blockers and mortality after myocardial</p><p>infarction in patients without heart failure: multicentre prospective cohort</p><p>study. BMJ 2016;354:i4801.</p><p>221. Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD, DiNicolantonio</p><p>JJ, Devereaux PJ, Alexander KP, Wetterslev J, Messerli FH. Clinical outcomes</p><p>with beta-blockers for myocardial infarction: a meta-analysis of randomized tri-</p><p>als. Am J Med 2014;127:939�953.</p><p>222. Hong J, Barry AR. Long-term beta-blocker therapy after myocardial infarction</p><p>in the reperfusion era: a systematic review. Pharmacotherapy 2018;38:546�554.</p><p>223. Tsujimoto T, Kajio H, Shapiro MF, Sugiyama T. Risk of all-cause mortality in dia-</p><p>betic patients taking beta-blockers. Mayo Clin Proc 2018;93:409�418.</p><p>ESC Guidelines 467</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://www.nice.org.uk/guidance/cg126</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>224. Sorbets E, Steg PG, Young R, Danchin N, Greenlaw N, Ford I, Tendera M,</p><p>Ferrari R, Merkely B, Parkhomenko A, Reid C, Tardif JC, Fox KM. b-blockers,</p><p>calcium antagonists, and mortality in stable coronary artery disease: an interna-</p><p>tional cohort study. Eur Heart J 2018:40;1399�1407.</p><p>225. Neumann A, Maura G, Weill A, Alla F, Danchin N. Clinical events after discon-</p><p>tinuation of beta-blockers in patients without heart failure optimally treated</p><p>after acute myocardial infarction: a cohort study on the French healthcare data-</p><p>bases. Circ Cardiovasc Qual Outcomes 2018;11:e004356.</p><p>226. Pascual I, Moris C, Avanzas P. Beta-blockers and calcium channel blockers: first</p><p>line agents. Cardiovasc Drugs Ther 2016;30:357�365.</p><p>227. Cooper-DeHoff RM, Chang SW, Pepine CJ. Calcium antagonists in the treat-</p><p>ment of coronary artery disease. Curr Opin Pharmacol 2013;13:301�308.</p><p>228. Padala SK, Lavelle MP, Sidhu MS, Cabral KP, Morrone D, Boden WE, Toth PP.</p><p>Antianginal therapy for stable ischemic heart disease: a contemporary review.</p><p>J Cardiovasc Pharmacol Ther 2017;22:499�510.</p><p>229. Rehnqvist N, Hjemdahl P, Billing E, Bjorkander I, Eriksson SV, Forslund L, Held</p><p>C, Nasman P, Wallen NH. Effects of metoprolol vs verapamil in patients with</p><p>stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur</p><p>Heart J 1996;17:76�81.</p><p>230. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli</p><p>FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA,</p><p>Kolb HR, Bakris GL, Cohen JD, Parmley WW; INVEST Investigators. A calcium</p><p>antagonist vs a non-calcium antagonist hypertension treatment strategy for</p><p>patients with coronary artery disease. The International Verapamil-Trandolapril</p><p>Study (INVEST): a randomized controlled trial. JAMA 2003;290:2805�2816.</p><p>231. Ried LD, Tueth MJ, Handberg E, Kupfer S, Pepine CJ; INVEST Study Group. A</p><p>Study of Antihypertensive Drugs and Depressive Symptoms (SADD-Sx)</p><p>in</p><p>patients treated with a calcium antagonist versus an atenolol hypertension</p><p>treatment strategy in the International Verapamil SR-Trandolapril Study</p><p>(INVEST). Psychosom Med 2005;67:398�406.</p><p>232. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N,</p><p>Just H, Fox KA, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG,</p><p>Dart AM, Hildebrandt P, Hjalmarson A, Kragten JA, Molhoek GP, Otterstad JE,</p><p>Seabra-Gomes R, Soler-Soler J, Weber S, Coronary disease Trial Investigating</p><p>Outcome with Nifedipine gastrointestinal therapeutic system investigators.</p><p>Effect of long-acting nifedipine on mortality and cardiovascular morbidity in</p><p>patients with stable angina requiring treatment (ACTION trial): randomised</p><p>controlled trial. Lancet 2004;364:849�857.</p><p>233. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi</p><p>H, Buebendorf E, Topol EJ; CAMELOT Investigators. Effect of antihypertensive</p><p>agents on cardiovascular events in patients with coronary disease and normal</p><p>blood pressure: the CAMELOT study: a randomized controlled trial. JAMA</p><p>2004;292:2217�2225.</p><p>234. Frishman WH, Glasser S, Stone P, Deedwania PC, Johnson M, Fakouhi TD.</p><p>Comparison of controlled-onset, extended-release verapamil with amlodipine</p><p>and amlodipine plus atenolol on exercise performance and ambulatory ischemia</p><p>in patients with chronic stable angina pectoris. Am J Cardiol 1999;83:507�514.</p><p>235. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators.</p><p>Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in</p><p>patients with chronic stable angina. Eur Heart J 2005;26:2529�2536.</p><p>236. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabra-</p><p>dine compared with amlodipine in patients with stable effort angina pectoris: a</p><p>3-month randomised, double-blind, multicentre, noninferiority trial. Drugs</p><p>2007;67:393�405.</p><p>237. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE Study Investigators. Efficacy of</p><p>the I(f) current inhibitor ivabradine in patients with chronic stable angina receiv-</p><p>ing beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur</p><p>Heart J 2009;30:540�548.</p><p>238. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators.</p><p>Ivabradine for patients with stable coronary artery disease and left-ventricular</p><p>systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-</p><p>controlled trial. Lancet 2008;372:807�816.</p><p>239. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators.</p><p>Ivabradine in stable coronary artery disease without clinical heart failure. N Engl</p><p>J Med 2014;371:1091�1099.</p><p>240. European Medicines Agency. European Medicines Agency recommends meas-</p><p>ures to reduce risk of heart problems with Corlentor/Procoralan (ivabradine).</p><p>https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-</p><p>measures-reduce-risk-heart-problems-corlentorprocoralan (28 March 2019).</p><p>241. Doring G. Antianginal and anti-ischemic efficacy of nicorandil in comparison</p><p>with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multi-</p><p>center, double-blind, randomized studies with stable coronary heart disease</p><p>patients. J Cardiovasc Pharmacol 1992;20:S74�S81.</p><p>242. Di Somma S, Liguori V, Petitto M, Carotenuto A, Bokor D, de Divitiis O, de</p><p>Divitiis M. A double-blind comparison of nicorandil and metoprolol in stable</p><p>effort angina pectoris. Cardiovasc Drugs Ther 1993;7:119�123.</p><p>243. Zhu WL, Shan YD, Guo JX, Wei JP, Yang XC, Li TD, Jia SQ, He Q, Chen JZ,</p><p>Wu ZG, Li ZQ, You K. Double-blind, multicenter, active-controlled, random-</p><p>ized clinical trial to assess the safety and efficacy of orally administered nicoran-</p><p>dil in patients with stable angina pectoris in China. Circ J 2007;71:826�833.</p><p>244. Jiang J, Li Y, Zhou Y, Li X, Li H, Tang B, Dai X, Ma T, Li L, Huo Y. Oral nicoran-</p><p>dil reduces ischemic attacks in patients with stable angina: a prospective, multi-</p><p>center, open-label, randomized, controlled study. Int J Cardiol</p><p>2016;224:183�187.</p><p>245. Medicines & Healthcare products Regulatory Agency (MHRA). Public</p><p>Assessment Report. UKPAR. Nicorandil 10 mg Tablets. Nicorandil 20 mg</p><p>Tablets. http://www.mhra.gov.uk/home/groups/par/documents/websiteresour</p><p>ces/con786861.pdf (28 March 2019).</p><p>246. IONA Study Group. Effect of nicorandil on coronary events in patients with</p><p>stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial.</p><p>Lancet 2002;359:1269�1275.</p><p>247. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A,</p><p>Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E; MERLIN-TIMI 36</p><p>Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in</p><p>patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI</p><p>36 randomized trial. JAMA 2007;297:1775�1783.</p><p>248. Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E,</p><p>Buros JL, Chaitman BR, Morrow DA. Efficacy of ranolazine in patients with</p><p>chronic angina observations from the randomized, double-blind, placebo-con-</p><p>trolled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in</p><p>Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll</p><p>Cardiol 2009;53:1510�1516.</p><p>249. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O,</p><p>Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman BR. Evaluation of ranola-</p><p>zine in patients with type 2 diabetes mellitus and chronic stable angina: results</p><p>from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of</p><p>Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol</p><p>2013;61:2038�2045.</p><p>250. Alexander KP, Weisz G, Prather K, James S, Mark DB, Anstrom KJ, Davidson-</p><p>Ray L, Witkowski A, Mulkay AJ, Osmukhina A, Farzaneh-Far R, Ben-Yehuda O,</p><p>Stone GW, Ohman EM. Effects of ranolazine on angina and quality of life after</p><p>percutaneous coronary intervention with incomplete revascularization: results</p><p>from the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial.</p><p>Circulation 2016;133:39�47.</p><p>251. Weisz G, Genereux P, Iniguez A, Zurakowski A, Shechter M, Alexander KP,</p><p>Dressler O, Osmukhina A, James S, Ohman EM, Ben-Yehuda O, Farzaneh-Far</p><p>R, Stone GW; RIVER-PCI investigators. Ranolazine in patients with incomplete</p><p>revascularisation after percutaneous coronary intervention (RIVER-PCI): a mul-</p><p>ticentre, randomised, double-blind, placebo-controlled trial. Lancet</p><p>2016;387:136�145.</p><p>252. McCarthy CP, Mullins KV, Kerins DM. The role of trimetazidine in cardiovascu-</p><p>lar disease: beyond an anti-anginal agent. Eur Heart J Cardiovasc Pharmacother</p><p>2016;2:266�272.</p><p>253. European Medicines Agency. Questions and answers on the review of medi-</p><p>cines containing trimetazidine (20 mg tablets, 35 mg modified release tablet and</p><p>20 mg/ml oral solution). https://www.ema.europa.eu/en/documents/referral/</p><p>questions-answers-review-medicines-containing-trimetazidine-20-mg-tablets-</p><p>35-mg-modified-release/ml-oral-solution_en.pdf (28 March 2019).</p><p>254. European Medicines Agency. Assessment Report for trimetazidine containing</p><p>medicinal products. https://www.ema.europa.eu/en/documents/referral/trimeta</p><p>zidine-article-31-referral-assessment-report_en.pdf (28 March 2019).</p><p>255. Peng S, Zhao M, Wan J, Fang Q, Fang D, Li K. The efficacy of trimetazidine on</p><p>stable angina pectoris: a meta-analysis of randomized clinical trials. Int J Cardiol</p><p>2014;177:780�785.</p><p>256. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allo-</p><p>purinol on exercise in patients with chronic stable angina: a randomised, pla-</p><p>cebo controlled crossover trial. Lancet 2010;375:2161�2167.</p><p>257. Singh JA, Yu S. Allopurinol reduces the risk of myocardial infarction (MI) in the</p><p>elderly: a study of Medicare claims. Arthritis Res Ther 2016;18:209.</p><p>258. Okafor ON, Farrington K, Gorog DA. Allopurinol as a therapeutic option in</p><p>cardiovascular disease. Pharmacol Ther 2017;172:139�150.</p><p>259. Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q,</p><p>Pepine CJ. Impact of resting heart rate on outcomes in hypertensive patients</p><p>with coronary</p><p>artery disease: findings from the INternational VErapamil-SR/</p><p>trandolapril STudy (INVEST). Eur Heart J 2008;29:1327�1334.</p><p>260. Tuunanen H, Engblom E, Naum A, Nagren K, Scheinin M, Hesse B, Juhani</p><p>Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J.</p><p>Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in</p><p>idiopathic dilated cardiomyopathy. Circulation 2008;118:1250�1258.</p><p>261. Ho JE, Bittner V, Demicco DA, Breazna A, Deedwania PC, Waters DD.</p><p>Usefulness of heart rate at rest as a predictor of mortality, hospitalization for</p><p>heart failure, myocardial infarction, and stroke in patients with stable coronary</p><p>468 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-measures-reduce-risk-heart-problems-corlentorprocoralan</p><p>https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-measures-reduce-risk-heart-problems-corlentorprocoralan</p><p>http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con786861.pdf</p><p>http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con786861.pdf</p><p>https://www.ema.europa.eu/en/documents/referral/questions-answers-review-medicines-containing-trimetazidine-20-mg-tablets-35-mg-modified-release/ml-oral-solution_en.pdf</p><p>https://www.ema.europa.eu/en/documents/referral/questions-answers-review-medicines-containing-trimetazidine-20-mg-tablets-35-mg-modified-release/ml-oral-solution_en.pdf</p><p>https://www.ema.europa.eu/en/documents/referral/questions-answers-review-medicines-containing-trimetazidine-20-mg-tablets-35-mg-modified-release/ml-oral-solution_en.pdf</p><p>https://www.ema.europa.eu/en/documents/referral/trimetazidine-article-31-referral-assessment-report_en.pdf</p><p>https://www.ema.europa.eu/en/documents/referral/trimetazidine-article-31-referral-assessment-report_en.pdf</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>heart disease (Data from the Treating to New Targets [TNT] trial). Am J Cardiol</p><p>2010;105:905�911.</p><p>262. Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T,</p><p>Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y,</p><p>Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel</p><p>R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP; ORBITA investiga-</p><p>tors. Percutaneous coronary intervention in stable angina (ORBITA): a double-</p><p>blind, randomised controlled trial. Lancet 2018;391:31�40.</p><p>263. Nossaman VE, Nossaman BD, Kadowitz PJ. Nitrates and nitrites in the treat-</p><p>ment of ischemic cardiac disease. Cardiol Rev 2010;18:190�197.</p><p>264. Davies RF, Habibi H, Klinke WP, Dessain P, Nadeau C, Phaneuf DC, Lepage S,</p><p>Raman S, Herbert M, Foris K, Linden W, Buttars JA; Canadian Amlodipine/ate-</p><p>nolol In Silent Ischemia Study (CASIS). Effect of amlodipine, atenolol and their</p><p>combination on myocardial ischemia during treadmill exercise and ambulatory</p><p>monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS)</p><p>Investigators. J Am Coll Cardiol 1995;25:619�625.</p><p>265. Salazar CA, Basilio Flores JE, Veramendi Espinoza LE, Mejia Dolores JW, Rey</p><p>Rodriguez DE, Loza Munarriz C. Ranolazine for stable angina pectoris. Cochrane</p><p>Database Syst Rev 2017;2:CD011747.</p><p>266. Badran HM, Ibrahim WA, Faheem N, Yassin R, Alashkar T, Yacoub M.</p><p>Provocation of left ventricular outflow tract obstruction using nitrate inhalation</p><p>in hypertrophic cardiomyopathy: relation to electromechanical delay. Glob</p><p>Cardiol Sci Pract 2015;2015:15.</p><p>267. Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil</p><p>citrate potentiates the hypotensive effects of nitric oxide donor drugs in male</p><p>patients with stable angina. J Am Coll Cardiol 2000;36:25�31.</p><p>268. CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, Chrolavicius S, Diaz R,</p><p>Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ,</p><p>Widimsky P, Afzal R, Pogue J, Yusuf S. Dose comparisons of clopidogrel and</p><p>aspirin in acute coronary syndromes. N Engl J Med 2010;363:930�942.</p><p>269. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of rando-</p><p>mised trials of antiplatelet therapy for prevention of death, myocardial infarc-</p><p>tion, and stroke in high risk patients. BMJ 2002;324:71�86.</p><p>270. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins</p><p>R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T,</p><p>Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary</p><p>prevention of vascular disease: collaborative meta-analysis of individual partici-</p><p>pant data from randomised trials. Lancet 2009;373:1849�1860.</p><p>271. Aradi D, Storey RF, Kom�ocsi A, Trenk D, Gulba D, Kiss RG, Husted S, Bonello</p><p>L, Sibbing D, Collet JP, Huber K; Working Group on Thrombosis of the</p><p>European Society of Cardiology. Expert position paper on the role of platelet</p><p>function testing in patients undergoing percutaneous coronary intervention. Eur</p><p>Heart J 2014;35:209�215.</p><p>272. Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N,</p><p>Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon</p><p>C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C,</p><p>Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P,</p><p>Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K,</p><p>Wittes J, Baigent C. Vascular and upper gastrointestinal effects of non-steroidal</p><p>anti-inflammatory drugs: meta-analyses of individual participant data from rand-</p><p>omised trials. Lancet 2013;382:769�779.</p><p>273. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus</p><p>aspirin in patients at risk of ischaemic events (CAPRIE). Lancet</p><p>1996;348:1329�1339.</p><p>274. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, Katona BG,</p><p>Mahaffey KW, Norgren L, Jones WS, Blomster J, Millegard M, Reist C, Patel</p><p>MR; EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clo-</p><p>pidogrel in symptomatic peripheral artery disease. N Engl J Med</p><p>2017;376:32�40.</p><p>275. Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K,</p><p>Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A,</p><p>Kjeldsen K, Storey RF; ESC Working Group on Cardiovascular Pharmacology</p><p>and Drug Therapy and ESC Working Group on Thrombosis. Expert position</p><p>paper on the use of proton pump inhibitors in patients with cardiovascular dis-</p><p>ease and antithrombotic therapy. Eur Heart J 2013;34:1708�1713,</p><p>1713a�1713b.</p><p>276. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S,</p><p>Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G,</p><p>Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopi-</p><p>dogrel in patients with acute coronary syndromes. N Engl J Med</p><p>2007;357:2001�2015.</p><p>277. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG,</p><p>Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC,</p><p>Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL,</p><p>Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR,</p><p>Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteza M, McLendon</p><p>RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS,</p><p>Ohman EM; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute</p><p>coronary syndromes without revascularization. N Engl J Med</p><p>2012;367:1297�1309.</p><p>278. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R,</p><p>Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson</p><p>V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET</p><p>and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in</p><p>patients with stable coronary artery disease:</p><p>great number of guidelines have been issued in recent years by</p><p>the European Society of Cardiology (ESC), as well as by other soci-</p><p>eties and organizations. Because of their impact on clinical practice,</p><p>quality criteria for the development of guidelines have been estab-</p><p>lished in order to make all decisions transparent to the user. The rec-</p><p>ommendations for formulating and issuing ESC Guidelines can be</p><p>found on the ESC website (http://www.escardio.org/Guidelines-&-</p><p>Education/Clinical-Practice-Guidelines/Guidelines-development/</p><p>Writing-ESC-Guidelines). The ESC Guidelines represent the offi-</p><p>cial position of the ESC on a given topic and are regularly updated.</p><p>The ESC carries out a number of registries which are essential to</p><p>assess, diagnostic/therapeutic processes, use of resources and adher-</p><p>ence to Guidelines. These registries aim at providing a better under-</p><p>standing of medical practice in Europe and around the world, based</p><p>on data collected during routine clinical practice.</p><p>The guidelines are developed together with derivative educational</p><p>material addressing the cultural and professional needs for cardiolo-</p><p>gists and allied professionals. Collecting high-quality observational</p><p>data, at appropriate time interval following the release of ESC</p><p>Guidelines, will help evaluate the level of implementation of the</p><p>Guidelines, checking in priority the key end points defined with the</p><p>ESC Guidelines and Education Committees and Task Force members</p><p>in charge.</p><p>The Members of this Task Force were selected by the ESC,</p><p>including representation from its relevant ESC sub-specialty</p><p>groups, in order to represent professionals involved with the</p><p>medical care of patients with this pathology. Selected experts in</p><p>the field undertook a comprehensive review of the published evi-</p><p>dence for management of a given condition according to ESC</p><p>Committee for Practice Guidelines (CPG) policy. A critical evalua-</p><p>tion of diagnostic and therapeutic procedures was performed,</p><p>including assessment of the riskbenefit ratio. The level of evidence</p><p>and the strength of the recommendation of particular manage-</p><p>ment options were weighed and graded according to predefined</p><p>scales, as outlined in Tables 1 and 2.</p><p>The experts of the writing and reviewing panels provided declara-</p><p>tion of interest forms for all relationships that might be perceived as</p><p>ESC Guidelines 411</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines</p><p>http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines</p><p>http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines</p><p>http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..real or potential sources of conflicts of interest. These forms were</p><p>compiled into one file and can be found on the ESC website (http://</p><p>www.escardio.org/guidelines). Any changes in declarations of interest</p><p>that arise during the writing period were notified to the ESC and</p><p>updated. The Task Force received its entire financial support from</p><p>the ESC without any involvement from the healthcare industry.</p><p>The ESC CPG supervises and coordinates the preparation of</p><p>new Guidelines. The Committee is also responsible for the</p><p>endorsement process of these Guidelines. The ESC Guidelines</p><p>undergo extensive review by the CPG and external experts. After</p><p>appropriate revisions the Guidelines are approved by all the</p><p>experts involved in the Task Force. The finalized document is</p><p>approved by the CPG for publication in the European Heart</p><p>Journal. The Guidelines were developed after careful considera-</p><p>tion of the scientific and medical knowledge and the evidence</p><p>available at the time of their dating.</p><p>Table 1 Classes of recommendations</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>C</p><p>la</p><p>ss</p><p>es</p><p>o</p><p>f r</p><p>ec</p><p>om</p><p>m</p><p>en</p><p>da</p><p>tio</p><p>ns</p><p>Class I Evidence and/or general agreement</p><p>that a given treatment or procedure is</p><p>Is recommended or is indicated</p><p>Wording to use</p><p>Class III Evidence or general agreement that the</p><p>given treatment or procedure is not</p><p>useful/effective, and in some cases</p><p>may be harmful.</p><p>Is not recommended</p><p>Class IIb</p><p>established by evidence/opinion.</p><p>May be considered</p><p>Class IIa Weight of evidence/opinion is in Should be considered</p><p>Class II</p><p>Table 2 Levels of evidence</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>Level of</p><p>evidence A</p><p>Data derived from multiple randomized clinical trials</p><p>or meta-analyses.</p><p>Level of</p><p>evidence B</p><p>Data derived from a single randomized clinical trial</p><p>or large non-randomized studies.</p><p>Level of</p><p>evidence C</p><p>Consensus of opinion of the experts and/or small studies,</p><p>retrospective studies, registries.</p><p>412 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>http://www.escardio.org/guidelines</p><p>http://www.escardio.org/guidelines</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..The task of developing ESC Guidelines also includes the crea-</p><p>tion of educational tools and implementation programmes for the</p><p>recommendations including condensed pocket guideline versions,</p><p>summary slides, booklets with essential messages, summary cards</p><p>for non-specialists and an electronic version for digital applications</p><p>(smartphones, etc.). These versions are abridged and thus, for</p><p>more detailed information, the user should always access to the</p><p>full text version of the Guidelines, which is freely available via the</p><p>ESC website and hosted on the EHJ website. The National</p><p>Societies of the ESC are encouraged to endorse, translate and</p><p>implement all ESC Guidelines. Implementation programmes are</p><p>needed because it has been shown that the outcome of disease</p><p>may be favourably influenced by the thorough application of clini-</p><p>cal recommendations.</p><p>Health professionals are encouraged to take the ESC Guidelines</p><p>fully into account when exercising their clinical judgment, as well as in</p><p>the determination and the implementation of preventive, diagnostic</p><p>or therapeutic medical strategies. However, the ESC Guidelines do</p><p>not override in any way whatsoever the individual responsibility of</p><p>health professionals to make appropriate and accurate decisions in</p><p>consideration of each patient’s health condition and in consultation</p><p>with that patient or the patient’s caregiver where appropriate and/or</p><p>necessary. It is also the health professional’s responsibility to verify</p><p>the rules and regulations applicable in each country to drugs and devi-</p><p>ces at the time of prescription.</p><p>2 Introduction</p><p>Coronary artery disease (CAD) is a pathological process character-</p><p>ized by atherosclerotic plaque accumulation in the epicardial arteries,</p><p>whether obstructive or non-obstructive. This process can be modi-</p><p>fied by lifestyle adjustments, pharmacological therapies, and invasive</p><p>interventions designed to achieve disease stabilization or regression.</p><p>The disease can have long, stable periods but can also become unsta-</p><p>ble at any time, typically due to an acute atherothrombotic event</p><p>caused by plaque rupture or erosion. However, the disease is</p><p>chronic, most often progressive, and hence serious, even in clinically</p><p>apparently silent periods. The dynamic nature of the CAD process</p><p>results in various clinical presentations, which can be conveniently</p><p>Time</p><p>C</p><p>ar</p><p>di</p><p>ac</p><p>r</p><p>is</p><p>k</p><p>(d</p><p>ea</p><p>th</p><p>, M</p><p>I)</p><p>Higher risk with</p><p>insufficiently controlled</p><p>risk factors, suboptimal</p><p>lifestyle modifications</p><p>and/or medical therapy,</p><p>large area at risk of</p><p>myocardial ischaemia</p><p>Subclinical</p><p>phase</p><p>Recent diagnosis or</p><p>revascularization</p><p>Long-standing diagnosis</p><p>Lower risk with</p><p>optimally controlled risk</p><p>factors, lifestyle changes,</p><p>adequate therapy for</p><p>secondary prevention</p><p>(e.g. aspirin, statins, ACE</p><p>inhibitors) and</p><p>appropriate</p><p>revascularization</p><p>the ONSET/OFFSET study.</p><p>Circulation 2009;120:2577�2585.</p><p>279. Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, Emanuelsson H,</p><p>Cannon CP, Becker RC, Wallentin L. Inhibitory effects of ticagrelor compared</p><p>with clopidogrel on platelet function in patients with acute coronary syn-</p><p>dromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET</p><p>substudy. J Am Coll Cardiol 2010;56:1456�1462.</p><p>280. Storey RF, Bliden KP, Ecob R, Karunakaran A, Butler K, Wei C, Tantry U,</p><p>Gurbel PA. Earlier recovery of platelet function after discontinuation of treat-</p><p>ment with ticagrelor compared with clopidogrel in patients with high antiplate-</p><p>let responses. J Thromb Haemost 2011;9:1730�1737.</p><p>281. Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, Garcia-Garcia</p><p>HM, van Es GA, Serruys PW. Long-term ticagrelor monotherapy versus stand-</p><p>ard dual antiplatelet therapy followed by aspirin monotherapy in patients</p><p>undergoing biolimus-eluting stent implantation: rationale and design of the</p><p>GLOBAL LEADERS trial. EuroIntervention 2016;12:1239�1245.</p><p>282. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow</p><p>J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG,</p><p>Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor</p><p>versus clopidogrel in patients with acute coronary syndromes. N Engl J Med</p><p>2009;361:1045�1057.</p><p>283. Wallentin L, Lindholm D, Siegbahn A, Wernroth L, Becker RC, Cannon CP,</p><p>Cornel JH, Himmelmann A, Giannitsis E, Harrington RA, Held C, Husted S,</p><p>Katus HA, Mahaffey KW, Steg PG, Storey RF, James SK; PLATO study group.</p><p>Biomarkers in relation to the effects of ticagrelor in comparison with clopidog-</p><p>rel in non-ST-elevation acute coronary syndrome patients managed with or</p><p>without in-hospital revascularization: a substudy from the Prospective</p><p>Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation</p><p>2014;129:293�303.</p><p>284. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati</p><p>A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG,</p><p>Windecker S, Zamorano JL, Levine GN. 2017 ESC focused update on dual anti-</p><p>platelet therapy in coronary artery disease developed in collaboration with</p><p>EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease</p><p>of the European Society of Cardiology (ESC) and of the European Association</p><p>for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213�260.</p><p>285. Storey RF, Angiolillo DJ, Bonaca MP, Thomas MR, Judge HM, Rollini F,</p><p>Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R,</p><p>Braunwald E, Sabatine MS. Platelet inhibition with ticagrelor 60 mg versus 90</p><p>mg twice daily in the PEGASUS-TIMI 54 trial. J Am Coll Cardiol 2016;67:</p><p>1145�1154.</p><p>286. Storey RF, Bliden KP, Patil SB, Karunakaran A, Ecob R, Butler K, Teng R, Wei C,</p><p>Tantry US, Gurbel PA; ONSET/OFFSET Investigators. Incidence of dyspnea and</p><p>assessment of cardiac and pulmonary function in patients with stable coronary</p><p>artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/</p><p>OFFSET study. J Am Coll Cardiol 2010;56:185�193.</p><p>287. Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools F, Steg PG,</p><p>Khurmi NS, Emanuelsson H, Cooper A, Cairns R, Cannon CP, Wallentin L.</p><p>Characterization of dyspnoea in PLATO study patients treated with ticagrelor</p><p>or clopidogrel and its association with clinical outcomes. Eur Heart J</p><p>2011;32:2945�2953.</p><p>288. Orme RC, Parker WAE, Thomas MR, Judge HM, Baster K, Sumaya W, Morgan</p><p>KP, McMellon HC, Richardson JD, Grech ED, Wheeldon NM, Hall IR, Iqbal J,</p><p>Barmby D, Gunn JP, Storey RF. Study of two dose regimens of ticagrelor com-</p><p>pared with clopidogrel in patients undergoing percutaneous coronary interven-</p><p>tion for stable coronary artery disease (STEEL-PCI). Circulation</p><p>2018;138:1290�1300.</p><p>289. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG,</p><p>Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW,</p><p>Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow</p><p>TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators. Twelve or 30</p><p>months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med</p><p>2014;371:2155�2166.</p><p>290. Yeh RW, Kereiakes DJ, Steg PG, Windecker S, Rinaldi MJ, Gershlick AH, Cutlip</p><p>DE, Cohen DJ, Tanguay JF, Jacobs A, Wiviott SD, Massaro JM, Iancu AC, Mauri</p><p>L; DAPT Study Investigators. Benefits and risks of extended duration dual anti-</p><p>platelet therapy after PCI in patients with and without acute myocardial infarc-</p><p>tion. J Am Coll Cardiol 2015;65:2211�2221.</p><p>ESC Guidelines 469</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>291. Bhatt DL, Bonaca MP, Bansilal S, Angiolillo DJ, Cohen M, Storey RF, Im K,</p><p>Murphy SA, Held P, Braunwald E, Sabatine MS, Steg PG. Reduction in ischemic</p><p>events with ticagrelor in diabetic patients with prior myocardial infarction in</p><p>PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67:2732�2740.</p><p>292. Bansilal S, Bonaca MP, Cornel JH, Storey RF, Bhatt DL, Steg PG, Im K, Murphy</p><p>SA, Angiolillo DJ, Kiss RG, Parkhomenko AN, Lopez-Sendon J, Isaza D, Goudev</p><p>A, Kontny F, Held P, Jensen EC, Braunwald E, Sabatine MS, Oude Ophuis AJ.</p><p>Ticagrelor for secondary prevention of atherothrombotic events in patients</p><p>with multivessel coronary disease. J Am Coll Cardiol 2018;71:489�496.</p><p>293. Bonaca MP, Bhatt DL, Storey RF, Steg PG, Cohen M, Kuder J, Goodrich E,</p><p>Nicolau JC, Parkhomenko A, Lopez-Sendon J, Dellborg M, Dalby A, Spinar J,</p><p>Aylward P, Corbalan R, Abola MTB, Jensen EC, Held P, Braunwald E, Sabatine</p><p>MS. Ticagrelor for prevention of ischemic events after myocardial infarction in</p><p>patients with peripheral artery disease. J Am Coll Cardiol 2016;67:2719�2728.</p><p>294. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL,</p><p>Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-</p><p>Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F,</p><p>Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W,</p><p>Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L;</p><p>APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coro-</p><p>nary syndrome. N Engl J Med 2011;365:699�708.</p><p>295. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or</p><p>both after myocardial infarction. N Engl J Med 2002;347:969�974.</p><p>296. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P,</p><p>Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN,</p><p>Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2�TIMI 51</p><p>Investigators. Rivaroxaban in patients with a recent acute coronary syndrome.</p><p>N Engl J Med 2012;366:9�19.</p><p>297. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O,</p><p>Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas</p><p>LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-</p><p>Jaramillo P, O’Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G,</p><p>Stork S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ,</p><p>Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM,</p><p>Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz</p><p>F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or</p><p>without aspirin in stable cardiovascular disease. N Engl J Med</p><p>2017;377:1319�1330.</p><p>298. Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, Rockhold F,</p><p>Plotnikov A, Mundl H, Strony J, Sun X, Husted S, Tendera M, Montalescot G,</p><p>Bahit MC, Ardissino D, Bueno H, Claeys MJ, Nicolau JC, Cornel JH, Goto S,</p><p>Kiss RG, Guray U, Park DW, Bode C, Welsh RC,</p><p>Revascularization</p><p>12 month</p><p>post ACS</p><p>ACS</p><p>ACS</p><p>12 month</p><p>post ACS</p><p>12 month</p><p>post ACS</p><p>Revascularization</p><p>RevascularizationRevascularizationRevascularization</p><p>ACS</p><p>Higher risk with</p><p>insufficiently controlled</p><p>risk factors, suboptimal</p><p>lifestyle modifications</p><p>and/or medical therapy,</p><p>large area at risk of</p><p>myocardial ischaemia</p><p>Subclinical</p><p>phase</p><p>Recent diagnosis or</p><p>revascularization</p><p>(≤12 months)</p><p>Long-standing diagnosis</p><p>Lower risk with</p><p>optimally controlled risk</p><p>factors, lifestyle changes,</p><p>adequate therapy for</p><p>secondary prevention</p><p>(e.g. aspirin, statins, ACE</p><p>inhibitors) and</p><p>appropriate</p><p>revascularization</p><p>Revascularization</p><p>12 month</p><p>post ACS</p><p>ACS</p><p>ACS</p><p>12 month</p><p>post ACS</p><p>12 month</p><p>post ACS</p><p>Revascularization</p><p>Revascularization</p><p>ACS</p><p>?</p><p>©</p><p>ES</p><p>C</p><p>2</p><p>01</p><p>9</p><p>Figure 1 Schematic illustration of the natural history of chronic coronary syndromes. ACE = angiotensin-converting enzyme; ACS = acute coronary</p><p>syndromes; CCS = chronic coronary syndromes; MI = myocardial infarction.</p><p>ESC Guidelines 413</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..categorized as either acute coronary syndromes (ACS) or chronic</p><p>coronary syndromes (CCS). The Guidelines presented here refer to</p><p>the management of patients with CCS. The natural history of CCS is</p><p>illustrated in Figure 1.</p><p>The most frequently encountered clinical scenarios in patients</p><p>with suspected or established CCS are: (i) patients with suspected</p><p>CAD and ‘stable’ anginal symptoms, and/or dyspnoea (see section 3);</p><p>(ii) patients with new onset of heart failure (HF) or left ventricular</p><p>(LV) dysfunction and suspected CAD (see section 4); (iii) asympto-</p><p>matic and symptomatic patients with stabilized symptoms 1 year after initial</p><p>diagnosis or revascularization (see section 5.2); (v) patients with</p><p>angina and suspected vasospastic or microvascular disease (see sec-</p><p>tion 6); and (vi) asymptomatic subjects in whom CAD is detected at</p><p>screening (see section 7).</p><p>All of these scenarios are classified as a CCS but involve different risks</p><p>for future cardiovascular events [e.g. death or myocardial infarction</p><p>(MI)], and the risk may change over time. Development of an ACS may</p><p>acutely destabilize each of these clinical scenarios. The risk may increase</p><p>as a consequence of insufficiently controlled cardiovascular risk factors,</p><p>suboptimal lifestyle modifications and/or medical therapy, or unsuccess-</p><p>ful revascularization. Alternatively, the risk may decrease as a conse-</p><p>quence of appropriate secondary prevention and successful</p><p>revascularization. Hence, CCS are defined by the different evolutionary</p><p>phases of CAD, excluding situations in which an acute coronary artery</p><p>thrombosis dominates the clinical presentation (i.e. ACS).</p><p>In the present Guidelines, each section deals with the main clinical</p><p>scenarios of CCS. This structure aims to simplify the use of the</p><p>Guidelines in clinical practice. Additional information, tables, figures,</p><p>and references are available in the Supplementary Data on the ESC</p><p>website (www.escardio.org) as well as in The ESC Textbook of</p><p>Cardiovascular Medicine.</p><p>2.1 What is new in the 2019 Guidelines?</p><p>New/revised concepts in 2019</p><p>The Guidelines have been revised to focus on CCS instead of stable CAD.</p><p>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-</p><p>otic plaque accumulation and functional alterations of coronary circulation that can be modified by lifestyle, pharmacological therapies, and revascularization,</p><p>which result in disease stabilization or regression.</p><p>In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identified: (i) patients with suspected CAD and ‘stable’ anginal</p><p>symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized</p><p>symptoms 1 year after initial diagnosis or revasculariza-</p><p>tion; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.</p><p>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’</p><p>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</p><p>updated.</p><p>The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular</p><p>events and mortality.</p><p>ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.</p><p>New major recommendations in 2019</p><p>Basic testing, diagnostics, and risk assessment</p><p>Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnosing CAD in</p><p>symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.</p><p>I</p><p>It is recommended that selection of the initial non-invasive diagnostic test be based on the clinical likelihood of CAD and other patient</p><p>characteristics that influence test performance, local expertise, and the availability of tests.</p><p>I</p><p>Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional significance or is</p><p>not diagnostic.</p><p>I</p><p>Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and severe symptoms</p><p>refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indicates high event risk. Invasive func-</p><p>tional assessment must be available and used to evaluate stenoses before revascularization, unless very high grade (>90% diameter stenosis).</p><p>I</p><p>Invasive coronary angiography with the availability of invasive functional evaluation should be considered for confirmation of the diagnosis</p><p>of CAD in patients with an uncertain diagnosis on non-invasive testing.</p><p>IIa</p><p>Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or non-diagnostic. IIa</p><p>Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inability to cooperate</p><p>with breath-hold commands, or any other conditions make good image quality unlikely.</p><p>III</p><p>Continued</p><p>414 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehz425#supplementary-data</p><p>http://www.escardio.org</p><p>Antithrombotic therapy in patients with CCS and sinus rhythm</p><p>Addition of a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with a high</p><p>risk of ischaemic events and without high bleeding risk (see options in section 3.3.2).</p><p>IIa</p><p>Addition of a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at least a</p><p>moderately increased risk of ischaemic events and without high bleeding risk (see options in section 3.3.2).</p><p>IIb</p><p>Antithrombotic therapy in patients with CCS and AF</p><p>When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in preference to a</p><p>VKA.</p><p>I</p><p>Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and a CHA2DS2-</p><p>VASc score >_2 in males and >_3 in females.</p><p>I</p><p>Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF and a</p><p>CHA2DS2-VASc score of 1 in males and 2 in females.</p><p>IIa</p><p>Antithrombotic therapy in post-PCI patients with AF or another indication for OAC</p><p>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</p><p>mg o.d., or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy.</p><p>I</p><p>When rivaroxaban is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, rivar-</p><p>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-</p><p>let therapy.</p><p>IIa</p><p>When dabigatran is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, dabi-</p><p>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-</p><p>telet therapy</p><p>IIa</p><p>After uncomplicated PCI, early cessation (_1 month should be considered when the risk of stent thrombosis outweighs</p><p>the bleeding risk, with the total duration (70%.</p><p>IIa</p><p>Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with an OAC, aspirin,</p><p>and clopidogrel in patients with a moderate or high risk of stent thrombosis, irrespective of the type of stent used.</p><p>IIb</p><p>Other pharmacological therapy</p><p>Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC monotherapy</p><p>who are at high risk of gastrointestinal bleeding.</p><p>I</p><p>Lipid-lowering drugs: if goals are not achieved with the maximum tolerated dose of statin, combination with ezetimibe is recommended. I</p><p>Lipid-lowering drugs: for patients at very high risk who do not achieve their goals on a maximum tolerated dose of statin and ezetimibe,</p><p>combination with a PCSK9 inhibitor is recommended.</p><p>I</p><p>ACE inhibitors should be considered in CCS patients at very high risk of cardiovascular adverse events. IIa</p><p>The sodium-glucose co-transporter 2 inhibitors empagliflozin, canagliflozin, or dapagliflozin are recommended in patients with diabetes</p><p>mellitus and CVD.</p><p>I</p><p>A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes mellitus and CVD. I</p><p>Screening for CAD in asymptomatic subjects</p><p>Carotid ultrasound IMT for cardiovascular risk assessment is not recommended. III</p><p>Recommendations for treatment options for refractory angina</p><p>A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refractory to optimal</p><p>medical and revascularization strategies.</p><p>IIb</p><p>aClass of recommendation.</p><p>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</p><p>coronary syndromes; CHA2DS2-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled] � Vascular disease, Age 65�74 and Sex category</p><p>[Female]; CTA = computed tomography angiography; CVD = cardiovascular disease; HF = heart failure; IMT = intima-media thickness; LV = left ventricular; NOAC = non-vita-</p><p>min K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtili-</p><p>sin-kexin type 9; VKA = vitamin K antagonist.</p><p>ESC Guidelines 415</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..3 Patients with angina and/or</p><p>dyspnoea, and suspected coronary</p><p>artery disease</p><p>3.1 Basic assessment, diagnosis, and risk</p><p>assessment</p><p>The general approach for the initial diagnostic management of</p><p>patients with angina and suspected obstructive CAD is presented</p><p>in Figure 2. The diagnostic management approach includes six</p><p>steps. The first step is to assess the symptoms and signs, to</p><p>identify patients with possible unstable angina or other forms of</p><p>ACS (step 1). In patients without unstable angina or other ACS,</p><p>the next step is to evaluate the patient’s general condition and</p><p>quality of life (step 2). Comorbidities that could potentially influ-</p><p>ence therapeutic decisions are assessed and other potential</p><p>causes of the symptoms are considered. Step 3 includes basic test-</p><p>ing and assessment of LV function. Thereafter, the clinical likeli-</p><p>hood of obstructive CAD is estimated (step 4) and, on this basis,</p><p>diagnostic testing is offered to selected patients to establish the</p><p>diagnosis of CAD (step 5). Once a diagnosis of obstructive CAD</p><p>has been confirmed, the patient’s event risk will be determined</p><p>(step 6) as it has a major impact on the subsequent therapeutic</p><p>decisions.</p><p>Changes in major recommendations</p><p>2013 Classa 2019 Classa</p><p>Exercise ECG is recommendedas the initial test to estab-</p><p>lish a diagnosis of stable CAD in patients withsymptoms</p><p>of angina and intermediate PTP of CAD (15�65%), free</p><p>of anti-ischaemic drugs, unless they cannot exercise or</p><p>display ECG changes that make the ECG non-evaluable.</p><p>I</p><p>Exercise ECG is recommended for the assessment of exercise tol-</p><p>erance, symptoms, arrhythmias, BP response, and event risk in</p><p>selected patients.</p><p>I</p><p>Exercise ECG may be considered as an alternative test to rule-in</p><p>or rule-out CAD when other non-invasive or invasive imaging</p><p>methods are not available.</p><p>IIb</p><p>Exercise ECG should be considered in patients on treat-</p><p>ment to evaluate control of symptoms and ischaemia.</p><p>IIa</p><p>Exercise ECG may be considered in patients on treatment to evalu-</p><p>ate control of symptoms and ischaemia.</p><p>IIb</p><p>For second-line treatment it is recommended that long-</p><p>acting nitrates, ivabradine, nicorandil, or ranolazine are</p><p>added according to heart rate, BP, and tolerance.</p><p>IIa</p><p>Long-acting nitrates should be considered as a second-line treat-</p><p>ment option when initial therapy with a beta-blocker and/or a non-</p><p>DHP-CCB is contraindicated, poorly tolerated, or inadequate in</p><p>controlling angina symptoms.</p><p>IIa</p><p>For second-line treatment, trimetazidine may be</p><p>considered,</p><p>IIb</p><p>Nicorandil, ranolazine, ivabradine, or trimetazidine should be con-</p><p>sidered as a second-line treatment to reduce angina frequency and</p><p>improve exercise tolerance in subjects who cannot tolerate, have</p><p>contraindications to, or whose symptoms are not adequately con-</p><p>trolled by beta-blockers, CCBs, and long-acting nitrates.</p><p>IIa</p><p>In selected patients, the combination of a beta-blocker or a CCB</p><p>with second-line drugs (ranolazine, nicorandil, ivabradine, and tri-</p><p>metazidine) may be considered for first-line treatment according</p><p>to heart rate, BP, and tolerance.</p><p>IIb</p><p>In patients with suspected coronary microvascular angina:</p><p>intracoronary acetylcholine and adenosine with Doppler</p><p>measurements may be considered during coronary arte-</p><p>riography, if the arteriogram is visually normal, to assess</p><p>endothelium-dependent and non-endothelium-dependent</p><p>CFR, and detect microvascular/epicardial vasospasm.</p><p>IIb</p><p>Guidewire-based CFR and/or microcirculatory resistance</p><p>measure-</p><p>ments should be considered in patients with persistent symptoms,</p><p>but coronary arteries that are either angiographically normal or</p><p>have moderate stenoses with preserved iwFR/FFR.</p><p>IIa</p><p>Intracoronary acetylcholine with ECG monitoring may be consid-</p><p>ered during angiography, if coronary arteries are either angiograph-</p><p>ically normal or have moderate stenoses with preserved iwFR/FFR,</p><p>to assess microvascular vasospasm.</p><p>IIb</p><p>In patients with suspected coronary microvascular angina:</p><p>transthoracic Doppler echocardiography of the LAD,</p><p>with measurement of diastolic coronary blood flow fol-</p><p>lowing intravenous adenosine and at rest, may be consid-</p><p>ered for non-invasive measurement of CFR.</p><p>IIb</p><p>Transthoracic Doppler of the LAD, CMR, and PET may be consid-</p><p>ered for non-invasive assessment of CFR.</p><p>IIb</p><p>aClass of recommendation.</p><p>BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel blocker; CFR = coronary flow reserve; CMR = cardiac magnetic resonance; DHP-CCB = dihy-</p><p>dropyridine calcium channel blockers; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio (instant flow reserve); LAD = left anterior</p><p>descending; PET = positron emission tomography; PTP = pre-test probability.</p><p>416 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>.</p><p>After these steps, appropriate therapies are to be initiated,</p><p>which include lifestyle management (see section 3.2), medical</p><p>therapy (see section 3.3), and revascularization when indicated</p><p>(see section 3.4).</p><p>3.1.1. Step 1: Symptoms and signs</p><p>A careful history is the cornerstone of the diagnosis of angina. It</p><p>is possible to achieve a high degree of certainty on a diagnosis</p><p>based on history alone, although physical examination and objec-</p><p>tive tests are most often necessary to confirm the diagnosis,</p><p>exclude alternative diagnoses, and assess the severity of underly-</p><p>ing disease. The history should include any manifestation of cardi-</p><p>ovascular disease (CVD) and risk factors (i.e. family history of</p><p>CVD, dyslipidaemia, diabetes, hypertension, smoking, and other</p><p>lifestyle factors).</p><p>The characteristics of discomfort related to myocardial ischae-</p><p>mia (angina pectoris) may be divided into four categories: location,</p><p>character, duration, and relationship to exertion, and other</p><p>exacerbating or relieving factors. The discomfort caused by myo-</p><p>cardial ischaemia is usually located in the chest, near the sternum,</p><p>but may be felt anywhere from the epigastrium to the lower jaw</p><p>or teeth, between the shoulder blades, or in either arm to the</p><p>wrist and fingers. The discomfort is often described as pressure,</p><p>tightness, or heaviness; sometimes strangling, constricting, or</p><p>burning. It may be useful to ask the patient directly about the pres-</p><p>ence of ‘discomfort’ as many do not feel ‘pain’ or ‘pressure’ in their</p><p>chest. Shortness of breath may accompany angina, and chest dis-</p><p>comfort may also be accompanied by less-specific symptoms such</p><p>as fatigue or faintness, nausea, burning, restlessness, or a sense of</p><p>impending doom. Shortness of breath may be the sole symptom of</p><p>CAD and it may be difficult to differentiate this from shortness of</p><p>breath caused by other conditions.</p><p>The duration of the discomfort is brief—</p><p>may be</p><p>asymptomatic [includes palpation of peripheral pulses, and ausculta-</p><p>tion of carotid and femoral arteries, as well as assessment of the</p><p>ankle-brachial index (ABI)], and other signs of comorbid conditions</p><p>such as thyroid disease, renal disease, or diabetes. This should</p><p>be used in the context of other clinical information, such as the pres-</p><p>ence of cough or stinging pain, making CAD more unlikely. One</p><p>should also try to reproduce the symptoms by palpation10 and test</p><p>the effect of sublingual nitroglycerin in order to classify the symptoms</p><p>(Table 3).</p><p>3.1.1.1 Stable vs. unstable angina</p><p>Unstable angina may present in one of three ways: (i) as rest</p><p>angina, i.e. pain of characteristic nature and location occurring at</p><p>rest and for prolonged periods (>20 min); (ii) new-onset angina,</p><p>i.e. recent (2 months) onset of moderate-to-severe angina</p><p>(Canadian Cardiovascular Society grade II or III); or (iii) crescendo</p><p>angina, i.e. previous angina, which progressively increases in</p><p>severity and intensity, and at a lower threshold, over a short</p><p>period of time. Management of angina fulfilling these criteria is</p><p>dealt with in the ESC Guidelines for the management of ACS.11,12</p><p>New-onset angina is generally regarded as unstable angina; how-</p><p>ever, if angina occurs for the first time with heavy exertion and</p><p>subsides at rest, the suspected condition falls under the definition</p><p>of CCS rather than unstable angina. In patients with unstable</p><p>angina identified as being at low risk, it is recommended that the</p><p>diagnostic and prognostic algorithms presented in these</p><p>Guidelines be applied once the period of instability has subsided.11</p><p>Low-risk patients with unstable angina are characterized by no</p><p>recurrence of angina, no signs of HF, no abnormalities in the initial</p><p>or subsequent electrocardiogram (ECG), and no rise in troponin</p><p>levels.11 In this setting, a non-invasive diagnostic strategy is recom-</p><p>mended before deciding on an invasive strategy. Based on the defi-</p><p>nition above, stable and unstable angina may overlap, and many</p><p>CCS patients pass through a period of experiencing unstable</p><p>angina.</p><p>Table 4 Grading of effort angina severity according to the Canadian Cardiovascular Society</p><p>Grade Description of angina severity</p><p>I Angina only with strenuous exertion Presence of angina during strenuous, rapid, or prolonged ordinary</p><p>activity (walking or climbing the stairs).</p><p>II Angina with moderate exertion Slight limitation of ordinary activities when they are performed</p><p>rapidly, after meals, in cold, in wind, under emotional stress, or</p><p>during the first few hours after waking up, but also walking uphill,</p><p>climbing more than one flight of ordinary stairs at a normal pace,</p><p>and in normal conditions.</p><p>III Angina with mild exertion Having difficulties walking one or two blocks, or climbing one</p><p>flight of stairs, at normal pace and conditions.</p><p>IV Angina at rest No exertion needed to trigger angina.</p><p>Table 3 Traditional clinical classification of suspected</p><p>anginal symptoms</p><p>Typical angina Meets the following three characteristics:</p><p>(i) Constricting discomfort in the front of the chest or</p><p>in the neck, jaw, shoulder, or arm;</p><p>(ii) Precipitated by physical exertion;</p><p>(iii) Relieved by rest or nitrates within 5 min.</p><p>Atypical angina Meets two of these characteristics.</p><p>Non-anginal</p><p>chest pain</p><p>Meets only one or none of these characteristics.</p><p>418 ESC Guidelines</p><p>D</p><p>ow</p><p>nloaded from</p><p>https://academ</p><p>ic.oup.com</p><p>/eurheartj/article/41/3/407/5556137 by guest on 11 August 2021</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..</p><p>..3.1.1.2 Distinction between symptoms caused by epicardial vs. microvas-</p><p>cular/vasospastic disease</p><p>A distinction between symptoms caused by an epicardial stenosis and</p><p>symptoms caused by microvascular or vasospastic disease cannot be</p><p>made with reasonable certainty. Reliance on ischaemia testing or</p><p>depiction of the coronary anatomy is often unavoidable to exclude</p><p>obstructive CAD, which can be absent in symptomatic patients.13,14</p><p>A diagnostic workup for microvascular or vasospastic disease is dis-</p><p>cussed in section 6 of these Guidelines.</p><p>3.1.2 Step 2: Comorbidities and other causes of</p><p>symptoms</p><p>Before any testing is considered, one must assess the patient’s general</p><p>health, comorbidities, and quality of life. If revascularization is unlikely</p><p>to be an acceptable option, further testing may be reduced to a clini-</p><p>cally indicated minimum and appropriate therapy should be insti-</p><p>tuted, which may include a trial of antianginal medication even if a</p><p>diagnosis of CAD has not been fully demonstrated. Non-invasive</p><p>functional imaging for ischaemia may be an option if there is need to</p><p>verify the diagnosis (Figure 2).</p><p>If the pain is clearly non-anginal, other diagnostic testing may be</p><p>indicated to identify gastrointestinal, pulmonary, or musculoskeletal</p><p>causes of chest pain. Nevertheless, these patients should also</p><p>receive Guideline-based risk-factor modification based on commonly</p><p>applied risk charts such as SCORE (Systematic COronary Risk</p><p>Evaluation) (www.heartscore.org).15</p><p>3.1.3 Step 3: Basic testing</p><p>Basic (first-line) testing in patients with suspected CAD includes stand-</p><p>ard laboratory biochemical testing, a resting ECG, possible ambulatory</p><p>ECG monitoring, resting echocardiography, and, in selected patients, a</p><p>chest X-ray. Such testing can be done on an outpatient basis.</p><p>3.1.3.1 Biochemical tests</p><p>Laboratory investigations are used to identify possible causes of</p><p>ischaemia, to establish cardiovascular risk factors and associated</p><p>conditions, and to determine prognosis. Haemoglobin as part of a</p><p>full blood count and—where there is a clinical suspicion of a thy-</p><p>roid disorder—thyroid hormone levels provide information</p><p>related to possible causes of ischaemia. Fasting plasma glucose and</p><p>glycated haemoglobin (HbA1c) should be measured in every</p><p>patient with suspected CAD. If both are inconclusive, an additional</p><p>oral glucose tolerance test is recommended.16 Knowledge of glu-</p><p>cose metabolism is important because of the well-recognized asso-</p><p>ciation between diabetes and adverse cardiovascular outcome.</p><p>Patients with diabetes should be managed according to specific</p><p>Guidelines.15,16 A lipid profile, including total cholesterol, high-</p><p>density lipoprotein cholesterol, low-density lipoprotein cholesterol</p><p>(LDL-C), and triglycerides, should also be evaluated in any patient</p><p>with suspected CAD to establish the patient’s risk profile and</p><p>ascertain the need for treatment.15,17 To characterize severe dysli-</p><p>pidaemia or follow-up on high triglyceridaemia, fasting values are</p><p>recommended.17</p><p>Peripheral artery disease (PAD) and renal dysfunction increase the</p><p>likelihood of CAD, and have a negative impact on prognosis.18�20</p><p>Hence, baseline renal function should be evaluated with estimation of</p><p>the glomerular filtration rate (GFR). It may also be reasonable to</p><p>measure the uric acid level, as hyperuricaemia is a frequent comorbid</p><p>condition and may also affect renal function.</p><p>If there is a clinical suspicion of CAD instability, biochemical</p><p>markers of myocardial injury—such as troponin T or troponin I—</p><p>should be measured, preferably using high-sensitivity assays, and</p><p>management should follow the Guidelines for ACS without persis-</p><p>tent ST-segment elevation.11 If high-sensitivity assays are employed,</p><p>low levels of troponin can be detected in many patients with stable</p><p>angina. Increased troponin levels are associated with adverse out-</p><p>come21�25 and small studies have indicated a possible incremental</p><p>value in diagnosing CAD,26,27 but larger trials are needed to verify</p><p>the utility of systematic assessment in patients suspected of CAD.</p><p>While multiple biomarkers may be useful for prognostication</p><p>(see section 5), they do not yet have a role in diagnosing obstructive</p><p>CAD.</p><p>Basic biochemistry testing in the initial diagnostic management of patients with suspected coronary artery disease</p><p>Recommendations</p>
- DOR TORÁCICA
- Doença Coronariana Crônica
- Aterosclerose e Isquemia Miocárdica
- PATO IC
- Protocolo Heparina Não Fracionada em BI
- CATARATAS RELACIONADA À IDADE
- Síndrome Coronariana Aguda
- ANALISE DE ECG
- Hipertensão sintomas e diagnostico
- Hipertensão Arterial e Insuficiência Cardíaca
- Infarto Agudo do Miocárdio
- Assistência em Afecções Cardiovasculares
- Assistência de Enfermagem em Cardiopatias
- Em relação às Diretrizes Brasileira de Hipertensão Arterial, podemos afirmar: I. A hipertensão arterial é uma condição multifatorial. II. A hiper...
- ¿Has telefoneado a Isabel? -Sí,
- As fibras alimentares possuem papel importante nos processos digestivos. Sendo assim, é correto dizer que I. o consumo excessivo de fibras insolúve...
- No contexto da insuficiência cardíaca, qual é a principal razão para a formação de edemas nos membros inferiores? A. Baixa produção de anticorpos ...
- No contexto da insuficiência cardíaca, qual é a principal razão para a formação de edemas nos membros inferiores? A. Aumento da frequência cardíac...
- Um paciente está em PCR. A fibrilação ventricular é refr Escolha a resposta correta e selecione Enviar. A. Atropina 1 mg IV/IO B. Epinefrina 1 mg I...
- A biossegurança inclui práticas que visam proteger:a) Pacientes, profissionais de saúde e a comunidade em geral.b) Apenas os profissionais de sa...
- O uso inadequado de antibióticos pode resultar em:a) Redução dos custos hospitalares.b) Aumento da resistência bacteriana.c) Prevenção de todas...
- Qual das opções abaixo NÃO é considerada uma IRAS comum?a) Pneumonia associada à ventilação mecânica.b) Infecção do trato urinário associada ao ...
- Acerca da biossegurança para os profissionais de saúde, assinale a opção correta.a) Diversos microrganismos são transmitidos, na falta de cuidado...
- Qual das seguintes intervenções é crucial para um paciente diagnosticado com insuficiência cardíaca congestiva?a) Restrição hídrica e controle de...
- Quais são os principais sinais e sintomas de uma crise hipertensiva?a) Dor torácica, cefaleia intensa, e visão turva.b) Edema periférico, icterí...
- Qual exame é essencial para monitorar a atividade elétrica do coração em pacientes com suspeita de doença cardíaca?a) Hemograma completo.b) Ultr...
- po_vermelha_revalida_objetiva_2014
- Estudo 1_Atualizado 2021
Perguntas dessa disciplina
Grátis
ESTÁCIO
Grátis
Qual dessas metas contém um indicador relativo? Grupo de escolhas da pergunta Alcançar 40.000 unidades produzidas em 2019 Aumentar a base de clie...
UNIASSELVI IERGS
Leia o trecho a seguir: “A escolha do tratamento da DAC do paciente idoso é, por vezes, bastante difícil. Cabe ao médico a introdução de medicação...
UNAMA
A partir do modelo acima, assinale a alternativa que apresenta uma forma de se escrever uma consulta em SQL (Structured Query Language) que mostre ...
Estudamos o escopo de aplicação da IN SGD/ME nº 1/2019 nas contratações públicas de TIC. Em relação à aplicabilidade do processo de contratação de ...
