Guidelines nste-acs-ft

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Guidelines nste-acs-ft

  1. 1. European Heart Journal (2007) 28, 1598–1660 doi:10.1093/eurheartj/ehm161 ESC GuidelinesGuidelines for the diagnosis and treatment ofnon-ST-segment elevation acute coronary syndromesThe Task Force for the Diagnosis and Treatment of Non-ST-SegmentElevation Acute Coronary Syndromes of the European Societyof CardiologyOnline publish-ahead-of-print 14 June 2007Authors/Task Force Members, Jean-Pierre Bassand* (Chair) (France), Christian W. Hamm* (Co-Chair) ´ ´(Germany), Diego Ardissino (Italy), Eric Boersma (The Netherlands), Andrzej Budaj (Poland), Francisco Fernandez-Aviles(Spain), Keith A.A. Fox (UK), David Hasdai (Israel), E. Magnus Ohman (USA), Lars Wallentin (Sweden), William Wijns(Belgium)ESC Committee for Practice Guidelines (CPG), Alec Vahanian (Chairperson) (France), John Camm (UK),Raffaele De Caterina (Italy), Veronica Dean (France), Kenneth Dickstein (Norway), Gerasimos Filippatos (Greece),Steen Dalby Kristensen (Denmark), Petr Widimsky (Czech Republic), Keith McGregor (France), Udo Sechtem (Germany), ´Michal Tendera (Poland), Irene Hellemans (The Netherlands), Jose Luis Zamorano Gomez (Spain), Sigmund Silber (Germany),Christian Funck-Brentano (France)Document Reviewers, Steen Dalby Kristensen (CPG Review Coordinator) (Denmark), Felicita Andreotti (Italy),Werner Benzer (Austria), Michel Bertrand (France), Amadeo Betriu (Spain), Raffaele De Caterina (Italy),Johan DeSutter (Belgium), Volkmar Falk (Germany), Antonio Fernandez Ortiz (Spain), Anselm Gitt (Germany),Yonathan Hasin (Israel), Kurt Huber (Austria), Ran Kornowski (Israel), Jose Lopez-Sendon (Spain), Joao Morais (Portugal),Jan Erik Nordrehaug (Norway), Sigmund Silber (Germany), Philippe Gabriel Steg (France), Kristian Thygesen (Denmark),Marco Tubaro (Italy), Alexander G.G. Turpie (Canada), Freek Verheugt (The Netherlands), Stephan Windecker (Switzerland)Table of ContentsPreamble . . . . . . . . . . . . . . . . . . . . . . . . . . . 1599 4.2 Diagnostic tools . . . . . . . . . . . . . . . . . . 1604 1. Introduction and definitions . . . . . . . . . . . . . 1600 4.2.1 Physical examination . . . . . . . . . . . . . 1604 2. Epidemiology and natural history . . . . . . . . . . 1601 4.2.2 Electrocardiogram . . . . . . . . . . . . . . . 1604 3. Pathophysiology . . . . . . . . . . . . . . . . . . . . 1601 4.2.3 Biochemical markers . . . . . . . . . . . . . 1604 3.1 The vulnerable plaque . . . . . . . . . . . . . . 1602 4.2.4 Echocardiography and non-invasive 3.2 Coronary thrombosis . . . . . . . . . . . . . . . 1602 myocardial imaging . . . . . . . . . . . . . . 1606 3.3 The vulnerable patient . . . . . . . . . . . . . . 1602 4.2.5 Imaging of the coronary anatomy . . . . . . 1607 3.4 Endothelial vasodilatory dysfunction . . . . . . 1602 4.3 Differential diagnoses . . . . . . . . . . . . . . 1607 3.5 Accelerated atherosclerosis . . . . . . . . . . . 1603 4.4 Risk scores . . . . . . . . . . . . . . . . . . . . . 1608 3.6 Secondary mechanisms . . . . . . . . . . . . . . 1603 5. Treatment . . . . . . . . . . . . . . . . . . . . . . . 1608 3.7 Myocardial injury . . . . . . . . . . . . . . . . . 1603 5.1 Anti-ischaemic agents . . . . . . . . . . . . . . 1608 4. Diagnosis and risk assessment . . . . . . . . . . . . 1603 5.1.1 Beta-blockers . . . . . . . . . . . . . . . . . 1608 4.1 Clinical presentation and history . . . . . . . . 1603 5.1.2 Nitrates . . . . . . . . . . . . . . . . . . . . . 1609 * Corresponding authors. Chair: Jean-Pierre Bassand, Department of Cardiology, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besancon, France. ¸Tel: þ33 381 668 539; fax: þ33 381 668 582. E-mail address: jean-pierre.bassand@ufc-chu.univ-fcomte.frCo-chair: Christian W. Hamm Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, Germany. Tel: þ49 6032 996 2202; fax: þ49 6032 996 2298. E-mail address: c.hamm@kerckhoff-klinik.deThe content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. Nopart of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of awritten request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they werewritten. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, overridethe individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with thatpatient, and where appropriate and necessary the patient’s guardian or carer. It is also the health professional’s responsibility to verify the rules and regulationsapplicable to drugs and devices at the time of prescription.& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
  2. 2. ESC Guidelines 1599 5.1.3 Calcium channel blockers . . . . . . . . . . 1609 7.4.3 Management of chronic kidney disease in 5.1.4 New drugs . . . . . . . . . . . . . . . . . . . 1609 patients with coronary artery disease . . . . 1638 5.2 Anticoagulants . . . . . . . . . . . . . . . . . . 1610 7.4.4 Biomarkers in chronic kidney disease . . . . 1638 5.2.1 Unfractionated heparin . . . . . . . . . . . . 1610 7.5 Anaemia . . . . . . . . . . . . . . . . . . . . . . 1638 5.2.2 Low molecular weight heparin . . . . . . . . 1610 7.6 Normal coronary arteries . . . . . . . . . . . . 1639 5.2.3 Factor-Xa inhibitors . . . . . . . . . . . . . . 1612 8. Management strategies . . . . . . . . . . . . . . . 1639 5.2.4 Direct thrombin inhibitors . . . . . . . . . . 1613 8.1 First step: initial evaluation . . . . . . . . . . . 1639 5.2.5 Vitamin K antagonists . . . . . . . . . . . . . 1614 8.2 Second step: diagnosis validation and 5.2.6 Anticoagulants during percutaneous risk assessment . . . . . . . . . . . . . . . . . . 1640 coronary intervention procedures in non-ST- 8.2.1 Diagnosis validation . . . . . . . . . . . . . . 1640 segment elevation acute coronary 8.2.2 Risk assessment . . . . . . . . . . . . . . . . 1640 syndromes . . . . . . . . . . . . . . . . . . . 1615 8.3 Third step: invasive strategy . . . . . . . . . . 1641 5.3 Antiplatelet agents . . . . . . . . . . . . . . . . 1616 8.3.1 Conservative strategy . . . . . . . . . . . . . 1641 5.3.1 Acetylsalicylic acid (aspirin) . . . . . . . . . 1616 8.3.2 Urgent invasive strategy . . . . . . . . . . . 1641 5.3.2 Thienopyridines . . . . . . . . . . . . . . . . 1617 8.3.3 Early invasive strategy . . . . . . . . . . . . 1641 5.3.3 Glycoprotein IIb/IIIa receptor inhibitors . . 1618 8.4 Fourth step: revascularization modalities . . . 1641 5.3.4 Resistance to antiplatelet agents/drug 8.5 Fifth step: discharge and post-discharge interactions . . . . . . . . . . . . . . . . . . 1621 management . . . . . . . . . . . . . . . . . . . 1641 5.3.5 Withdrawal of antiplatelet agents . . . . . . 1622 9. Performance measures . . . . . . . . . . . . . . . . 1643 5.4 Coronary revascularization . . . . . . . . . . . 1623 10. Abbreviations . . . . . . . . . . . . . . . . . . . . . 1644 5.4.1 Coronary angiography . . . . . . . . . . . . . 1623 11. Trial acronyms . . . . . . . . . . . . . . . . . . . . 1644 5.4.2 Invasive vs. conservative strategy . . . . . . 1623 Acknowledgements . . . . . . . . . . . . . . . . . . 1645 5.4.3 Percutaneous coronary intervention . . . . . 1625 References . . . . . . . . . . . . . . . . . . . . . . 1645 5.4.4 Coronary artery bypass graft . . . . . . . . . 1625 5.4.5 Respective indications for percutaneous coronary intervention or coronary artery bypass graft . . . . . . . . . . . . . . . . . . 1625 Preamble 5.5 Long-term management . . . . . . . . . . . . . 1626 Guidelines and Expert Consensus Documents summarize and 5.5.1 Lifestyle . . . . . . . . . . . . . . . . . . . . 1626 evaluate all currently available evidence on a particular issue 5.5.2 Weight reduction . . . . . . . . . . . . . . . 1626 with the aim to assist physicians in selecting the best manage- 5.5.3 Blood pressure control . . . . . . . . . . . . 1626 ment strategies for a typical patient, suffering from a given 5.5.4 Management of diabetes . . . . . . . . . . . 1626 condition, taking into account the impact on outcome, as 5.5.5 Interventions on lipid profile . . . . . . . . . 1626 well as the risk–benefit ratio of particular diagnostic or thera- 5.5.6 Antiplatelet agents and anticoagulants . . . 1627 peutic means. Guidelines are no substitutes for textbooks. The 5.5.7 Beta-blockers . . . . . . . . . . . . . . . . . 1627 legal implications of medical guidelines have been discussed 5.5.8 Angiotensin-converting enzyme inhibitors . 1627 previously. 5.5.9 Angiotensin-2 receptor blockers . . . . . . . 1628 A great number of Guidelines and Expert Consensus Docu- 5.5.10 Aldosterone receptor antagonists . . . . . 1628 ments have been issued in recent years by the European 5.6 Rehabilitation and return to Society of Cardiology (ESC) as well as by other societies physical activity . . . . . . . . . . . . . . . . . 1628 and organizations. Because of the impact on clinical prac- 6. Complications and their management . . . . . . . 1629 tice, quality criteria for development of guidelines have 6.1 Bleeding complications . . . . . . . . . . . . . . 1629 been established in order to make all decisions transparent 6.1.1 Predictors of bleeding risk . . . . . . . . . . 1629 to the user. The recommendations for formulating and 6.1.2 Impact of bleeding on prognosis . . . . . . . 1629 issuing ESC Guidelines and Expert Consensus Documents 6.1.3 Management of bleeding complications . . . 1630 can be found on the ESC website (http://www.escardio. 6.1.4 Impact of blood transfusion . . . . . . . . . 1631 org/knowledge/guidelines/rules). 6.2 Thrombocytopenia . . . . . . . . . . . . . . . . 1631 In brief, experts in the field are selected and undertake 6.2.1 Heparin-induced thrombocytopenia . . . . . 1632 a comprehensive review of the published evidence for 6.2.2 Glycoprotein IIb/inhibitor-induced management and/or prevention of a given condition. A criti- thrombocytopenia . . . . . . . . . . . . . . . 1632 cal evaluation of diagnostic and therapeutic procedures is 7. Special populations and conditions . . . . . . . . . 1632 performed including assessment of the risk–benefit ratio. 7.1 The elderly . . . . . . . . . . . . . . . . . . . . 1632 Estimates of expected health outcomes for larger societies 7.1.1 Early diagnostic evaluation in the elderly . 1633 are included, where data exist. The level of evidence and 7.1.2 Therapeutic considerations . . . . . . . . . . 1633 the strength of recommendation of particular treatment 7.2 Gender . . . . . . . . . . . . . . . . . . . . . . . 1633 options are weighed and graded according to pre-defined 7.2.1 Glycoprotein IIb/IIIa inhibitors in women . . 1634 scales, as outlined in Tables 1 and 2. 7.2.2 Revascularization and early invasive The experts of the writing panels have provided disclosure strategy among women . . . . . . . . . . . . 1635 statements of all relationships they may have which might 7.3 Diabetes mellitus . . . . . . . . . . . . . . . . . 1635 be perceived as real or potential sources of conflicts of 7.4 Chronic kidney disease . . . . . . . . . . . . . . 1636 interest. These disclosure forms are kept on file at the Euro- 7.4.1 Chronic kidney disease as a marker of risk of pean Heart House, headquarters of the ESC. Any changes in coronary artery disease . . . . . . . . . . . . 1636 conflict of interest that arise during the writing period must 7.4.2 Contrast-induced nephropathy . . . . . . . . 1637 be notified to the ESC. The Task Force report was entirely
  3. 3. 1600 ESC Guidelines and implementing them into clinical practice can then Table 1 Classes of recommendations only be completed if surveys and registries are performed to verify that real-life daily practice is in keeping with Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, and what is recommended in the guidelines. Such surveys and effective registries also make it possible to evaluate the impact Class II Conflicting evidence and/or a divergence of opinion of implementation of the guidelines on patient outcomes. about the usefulness/efficacy of the given Guidelines and recommendations should help physicians treatment or procedure to make decisions in their daily practice; however, the Class Weight of evidence/opinion is in favour of usefulness/ ultimate judgement regarding the care of an individual IIa efficacy patient must be made by the physician in charge of Class Usefulness/efficacy is less well established by his/her care. IIb evidence/opinion Class III Evidence or general agreement that the given treatment or procedure is not useful/effective and 1. Introduction and definitions in some cases may be harmful Cardiovascular diseases are presently the leading causes of death in industrialized countries and expected to become so in emerging countries by 2020.1 Among these, coronary Table 2 Levels of evidence artery disease (CAD) is the most prevalent manifestation and is associated with high mortality and morbidity. The Level of Data derived from multiple randomized clinical presentations of ischaemic heart disease include evidence A clinical trials or meta-analyses silent ischaemia, stable angina pectoris, unstable angina, Level of Data derived from a single randomized clinical myocardial infarction (MI), heart failure, and sudden death. evidence B trial or large non-randomized studies Patients with chest pain represent a very large proportion of Level of Consensus of opinion of the experts and/or all acute medical hospitalizations in Europe. Distinguishing evidence C small studies, retrospective studies, those with acute coronary syndrome (ACS) within the very registries large proportion with suspected cardiac pain represents a diagnostic challenge, especially in those without clear symp- toms or electrocardiographic features. In spite of modern treatment, the rates of death, MI, and re-admission ofsupported financially by the ESC and was developed without patients with ACS remain high.any involvement of the industry. It is well established that ACS in their different clinical pre- The ESC Committee for Practice Guidelines (CPG) super- sentations share a widely common pathophysiological sub-vises and coordinates the preparation of new Guidelines strate. Pathological, angioscopic, and biological observationsand Expert Consensus Documents produced by Task Forces, have demonstrated that atherosclerotic plaque rupture orexpert groups, or consensus panels. The Committee is also erosion, with differing degrees of superimposed thrombosisresponsible for the endorsement process of these Guide- and distal embolization, resulting in myocardial underperfu-lines and Expert Consensus Documents or statements. sion, represent the basic pathophysiological mechanisms inOnce the document has been finalized and approved by all most ACS.the experts involved in the Task Force, it is submitted to As this is a life-threatening state of atherothromboticoutside specialists for review. The document is revised, disease, criteria for risk stratification have been developedand finally approved by the CPG and subsequently published. to allow the clinician to make timely decisions on pharmaco- After publication, dissemination of the message is of para- logical management as well as on coronary revascularizationmount importance. Pocket-sized versions and personal strategies, tailored to the individual patient. The leadingdigital assistant (PDA)-downloadable versions are useful at symptom that initiates the diagnostic and therapeuticthe point of care. Some surveys have shown that the cascade is chest pain, but the classification of patients isintended end-users are sometimes not aware of the exist- based on the electrocardiogram (ECG). Two categories ofence of guidelines, or simply do not translate them into patients may be encountered:practice, so this is why implementation programmes fornew guidelines form an important component of the disse- (i) Patients with typical acute chest pain and persistentmination of knowledge. Meetings are organized by the ESC (>20 min) ST-segment elevation. This is termedand directed towards its member National Societies and ST-elevation ACS (STE-ACS) and generally reflects ankey opinion leaders in Europe. Implementation meetings acute total coronary occlusion. Most of these patientscan also be undertaken at national levels, once the guide- will ultimately develop an ST-elevation MI (STEMI).lines have been endorsed by the ESC member societies and The therapeutic objective is to achieve rapid,translated into the national language. Implementation pro- complete, and sustained reperfusion by primary angio-grammes are needed because it has been shown that the plasty or fibrinolytic therapy.2outcome of disease may be favourably influenced by the (ii) Patients with acute chest pain but without persistentthorough application of clinical recommendations. ST-segment elevation. They have rather persistent or Thus, the task of writing Guidelines or Expert Consensus transient ST-segment depression or T-wave inversion,documents covers not only the integration of the most flat T-waves, pseudo-normalization of T-waves, or norecent research, but also the creation of educational tools ECG changes at presentation. The initial strategy inand implementation programmes for the recommendations. these patients is to alleviate ischaemia and symp-The loop between clinical research, writing of guidelines, toms, to monitor the patient with serial ECG, and to
  4. 4. ESC Guidelines 1601 repeat measurements of markers of myocardial necro- 2. Epidemiology and natural history sis. At presentation, the working diagnosis of non-STE-ACS (NSTE-ACS), based on the measurement The diagnosis of NSTE-ACS is more difficult to establish than of troponins, will be further qualified into non-ST STEMI and therefore its prevalence is harder to estimate. In elevation MI (NSTEMI) or unstable angina. (Figure 1) addition, in recent years, a new definition of MI has been In a certain number of patients, CAD will subsequently introduced to take into account the use of more sensitive be excluded as the cause of symptoms. The thera- and more specific biomarkers of cell death.5 In this con- peutic management is guided by the final diagnosis. text, the prevalence of NSTE-ACS, relative to STEMI, has been determined from multiple surveys and registries.6–15 The management of patients with STEMI is addressed in Overall, data suggest that the annual incidence of NSTE-the ESC Guidelines for management of ST-elevation acute ACS is higher than that of STEMI. The ratio betweenMI.2 The present document deals with the management of NSTE-ACS and STEMI has changed over time, as the ratepatients with suspected NSTE-ACS, replacing the document of NSTE-ACS increased relative to STEMI, without any clearpublished in 2000 and last updated in 2002.3 It includes all explanation for the reasons behind this evolution.16 Thisscientific evidence fully published as peer-reviewed papers change in the pattern of NSTE-ACS could actually be linkedin a journal, before 30 April 2007. to changes in the management of disease and greater The class A level of recommendations of this document efforts in prevention of CAD over the last 20 years.17–20is based primarily on randomized, double-blind studies Overall, from these registries and surveys, it has beenof adequate size using contemporary adjunctive treatment shown that the annual incidence of hospital admissionsand endpoints that are not subject to observer bias, such for NSTE-ACS is in the range of 3 per 1000 inhabitants. Toas death and MI. These studies were considered to represent date, there are no clear estimates for Europe as a whole,the greatest weight of evidence. Studies that were random- because of the absence of a common centre for centralizedized, but not double blind, and/or studies using less health statistics. However, the incidence of the disease isrobust endpoints (such as refractory ischaemia or need greatly variable among European countries, with a strongfor revascularization) were considered to confer a lower west-to-east gradient, the higher incidences and deathweight of evidence. If only smaller studies were available, rates occurring in Central-Eastern Europe.meta-analyses were used. However, even the largest con- Overall, the prognosis of NSTE-ACS can be derived fromtrolled trials do not cover all aspects seen in real life. There- surveys carried out around the world that have includedfore, some recommendations are derived from subset more than 100 000 patients. Data consistently show thatanalyses of larger trials, in the absence of sufficiently the mortality rate at 1 and 6 months is higher in surveypowered independent studies. Furthermore, in this rapidly populations than in randomized clinical trials. Hospital mor-moving field, new studies will constantly challenge the tality is higher in patients with STEMI than among thosecurrent recommendations. with NSTE-ACS (7 vs. 5%, respectively), but, at 6 months, Costs of health care become an increasing issue in many the mortality rates are very similar in both conditionscountries. Although this should not play a role in decision- (12 vs. 13%, respectively).21,22 Long-term follow-up of thosemaking, cost consciousness is necessary today. Therefore, who survive to reach hospital showed that death rates werewe provide the numbers needed to treat (NNT) to prevent higher among those with NSTE-ACS than with STE-ACS, withan event for the most important treatment options. a two-fold difference at 4 years.23 This difference in mid-The NNT seems to be the most transparent approach to and long-term evolution may be due to different patientcompare studies of different size and different endpoints. profiles, since NSTE-ACS patients tend to be older, withFor example, an NNT of 50 to prevent one death is to be more co-morbidities, especially diabetes and renal failure.interpreted differently from an NNT of 50 to avoid one The difference could also be due to the greater extent ofrehospitalization.4 coronary artery and vascular disease or persistent triggering factors such as inflammation.24,25 The implications for therapy are as follows. † NSTE-ACS is more frequent than STEMI. † In contrast to STEMI, where most events occur before or shortly after presentation, in NSTE-ACS these events con- tinue over days and weeks. † Mortality of STEMI and NSTE-ACS after 6 months is comparable. This implies that treatment strategies for NSTE-ACS need to address the requirements of the acute phase as well as longer-term treatment. 3. Pathophysiology Atherosclerosis is a chronic, multifocal immunoinflamma- tory, fibroproliferative disease of medium-sized and large arteries mainly driven by lipid accumulation.26 CAD involves Figure 1 The spectrum of acute coronary syndromes. two distinct processes: a fixed and barely reversible
  5. 5. 1602 ESC Guidelinesprocess that causes gradual luminal narrowing slowly over from human fibrous caps, and protease inhibitors can blockdecades (atherosclerosis) and a dynamic and potentially this process.reversible process that punctuates the slow progression ina sudden and unpredictable way, causing rapid complete 3.2 Coronary thrombosisor partial coronary occlusion (thrombosis or vasospasm, orboth). Thus, symptomatic coronary lesions contain a vari- The central role of thrombosis in the development of ACS hasable mix of chronic atherosclerosis and acute thrombosis. been widely demonstrated by means of autopsy data31,32Since the exact nature of the mix is unknown in the individ- and angiographic and angioscopic detection of thrombi atual patient, the term atherothrombosis is frequently used. the site of the culprit lesion.33 In addition, the detection ofGenerally, atherosclerosis predominates in lesions respon- markers of thrombin generation and platelet activation34sible for chronic stable angina, whereas thrombosis constitu- and evidence of improved outcomes with antithrombotictes the critical component of culprit lesions responsible for treatments have contributed to our understanding of thethe ACS.27,28 role of thrombosis in ACS. ACS represent a life-threatening manifestation of athero- Coronary thrombosis in ACS usually develops at the site ofsclerosis usually precipitated by acute thrombosis, induced a vulnerable plaque. The lipid-rich core exposed afterby a ruptured or eroded atherosclerotic plaque, with or plaque rupture is highly thrombogenic and has a high con-without concomitant vasoconstriction, causing a sudden centration of tissue factor.35 Thrombosis is induced at theand critical reduction in blood flow. In the complex site of plaque rupture or erosion and may lead to rapidprocess of plaque disruption, inflammation was revealed changes in the severity of stenosis that may causeas a key pathophysiological element. In rare cases, ACS subtotal or total vessel occlusion. The thrombus is fibrin-may have a non-atherosclerotic aetiology such as arteritis, rich and completely occlusive in STEMI, whereas it istrauma, dissection, thrombo-embolism, congenital platelet-rich and partially or intermittently occlusive inanomalies, cocaine abuse, and complications of cardiac NSTE-ACS.catheterization. Some key pathophysiological elements will Spontaneous thrombolysis may explain transient episodesbe described in more detail because they are important to of thrombotic vessel occlusion/subocclusion and the associ-understand the therapeutic strategies. ated transient ischaemia. A platelet-rich thrombus at the site of plaque rupture may fragment into small particles, which embolize downstream and may occlude arterioles3.1 The vulnerable plaque and capillaries. These platelet emboli may cause smallAtherosclerosis is not a continuous, linear process but rather areas of necrosis in the myocardium supplied by the culprita disease with alternate phases of stability and instability. vessel, thus leading to the release of markers of myocardialSudden and unpredictable changes in symptoms appear necrosis.31,32to be related to plaque disruption. The plaques proneto instability and rupture have a large lipid core, a low 3.3 The vulnerable patientdensity of smooth muscle cells, a high concentration of There is increasing experimental and clinical evidence toinflammatory cells, and a thin fibrous cap covering the suggest the diffuse nature of unstable plaques in patientslipid core compared with stable plaques.29 Plaque vulner- with ACS. Multiple sites of plaque rupture with or withoutability may also depend on circumferential wall stress, intracoronary thrombosis, along with elevated levels ofon the location and size of the plaque, and on the impact of various systemic markers of inflammation and thrombosisflow on the luminal plaque surface. In addition to plaque as well as coagulation system activation, have been docu-rupture, plaque erosion is another underlying mechanism in mented in patients with ACS.36–38 Hypercholesterolaemia,ACS. When erosion occurs, the thrombus adheres to the tobacco smoking, and increased fibrinogen levels havesurface of the plaque, whereas in the case of plaque been reported to contribute to instability in these patients,rupture, the thrombus involves the deeper layers down to leading to thrombotic complications.the lipid core. This may contribute to the growth and rapid The concept of widespread instability has importantprogression of the plaque, if the thrombus is not accommo- therapeutic implications, because beyond the focal revascu-dated by positive remodelling. larization strategies, such individuals should have systemic The fibrous cap usually has a high concentration of type I therapies aimed at stabilizing the high-risk profile thatcollagen and can support high tensile stress without break- may cause recurrent ischaemic events.ing. However, it is a dynamic structure in continuous equili-brium between growth factor-modulated collagen synthesisand its degradation by proteases arising from activated 3.4 Endothelial vasodilatory dysfunctionmacrophages. The apoptosis of smooth muscle cells can Minor changes in coronary tone may greatly affect myocar-also weaken cap tissue and favour plaque rupture. Macro- dial blood supply and thus cause insufficient flow at rest orphage infiltration has been consistently demonstrated in during exercise. Vasospasm most frequently occurs at thepathological studies; the proportion of macrophages is six site of atherosclerotic plaques in which local vasoconstrict-to nine times greater in ruptured than in stable plaques ing substances, such as serotonin, thromboxane A2, andand is characterized by the presence of activated T- thrombin, are released locally by platelets and intracoron-lymphocytes at the site of plaque rupture that can release ary thrombi. It has been shown that the endothelium is avarious cytokines that activate macrophages and promote multifunctional organ, the integrity of which is essentialsmooth muscle cell proliferation.30 These cells may pro- for normal tone modulation. Endothelial dysfunction isduce proteases that digest the extracellular matrix. In vitro, linked to prognosis and is unmasked by vasoconstrictionmacrophages induce the breakdown of collagen obtained induced by acetylcholine and methacholine.39,40 The
  6. 6. ESC Guidelines 1603prototype of dynamic coronary obstruction as a cause of ACS 4.1 Clinical presentation and historyis Prinzmetal’s variant angina, in which coronary vasospasm The clinical presentation of NSTE-ACS encompasses a wideis the main determinant of an abrupt reduction in flow. This variety of symptoms. Traditionally, several clinical presenta-usually occurs at sites of critical or subcritical stenoses.41 tions have been distinguished:3.5 Accelerated atherosclerosis † Prolonged (.20 min) anginal pain at rest,Severe endothelial injury appears to be the critical initiating † New onset (de novo) severe angina [Class III of the Classi-event that causes smooth muscle cell proliferation in accel- fication of the Canadian Cardiovascular Society45 (CCS)]erated atherosclerosis. This is followed by intense platelet † Recent destabilization of previously stable angina with atactivation and thrombus formation leading to rapidly pro- least CCS III angina characteristics (crescendo angina), orgressive coronary narrowing. An angiographic study of † Post-MI angina.patients on the waiting list for percutaneous coronary revas-cularization has shown that rapid progression of pre-existing Prolonged pain is observed in 80% of patients, whereas deatherosclerotic stenoses is relatively common, and the risk novo or accelerated angina is observed in only 20%.46 It isarising from complex stenoses is greater than that associ- important to note that a reliable distinction between ACSated with smooth lesions.42 with or without ST-elevation cannot be based on symptoms. The typical clinical presentation of NSTE-ACS is retro- sternal pressure or heaviness (‘angina’) radiating to the3.6 Secondary mechanisms left arm, neck, or jaw, which may be intermittent (usuallyA number of extra-cardiac mechanisms can cause a critical lasting several minutes) or persistent. These complaintsincrease in myocardial oxygen consumption to above the may be accompanied by other symptoms such as dia-supply threshold, and thus elicit an ACS episode with or phoresis, nausea, abdominal pain, dyspnoea, and syncope.without a pre-existing coronary stenosis. The mechanisms However, atypical presentations of NSTE-ACS are not uncom-related to an increase in myocardial oxygen consumption mon.47 These include epigastric pain, recent-onset indiges-are fever, tachycardia, thyrotoxicosis, a hyperadrenergic tion, stabbing chest pain, chest pain with some pleuriticstate, sudden emotional stress, and increased left ventricu- features, or increasing dyspnoea. Atypical complaints arelar (LV) afterload (hypertension, aortic stenosis), whereas often observed in younger (25–40 years) and older (.75those related to reduced myocardial oxygen delivery are years) patients, in women, and in patients with diabetes,anaemia, methaemoglobinaemia, and hypoxaemia. Triggers chronic renal failure, or dementia.47,48 Absence of chestsuch as emotional upset, vigorous physical exercise, lack pain leads to under-recognition of the disease and under-of sleep, or overeating have been shown to precipitate the treatment.49 The diagnostic and therapeutic challengesonset of ACS.43 arise especially when the ECG is normal or nearly normal, or conversely when the ECG is abnormal at baseline due to underlying conditions such as intraventricular conduction3.7 Myocardial injury defects or LV hypertrophy.13Pathological studies in patients with NSTE-ACS show a broad There are certain features regarding the symptomsspectrum of findings in the myocardium supplied by the that may support the diagnosis of CAD and guide the man-culprit vessel. The myocardium may be normal or there agement. The exacerbation of symptoms by physical exer-may be varying degrees of necrosis. In some patients, tion or their relief at rest or after nitrates support afocal areas of cell necrosis in the myocardium supplied by diagnosis of ischaemia. Symptoms at rest carry a worse prog-the culprit artery have been shown, which have been attrib- nosis than symptoms elicited only during physical exertion.uted to repeated episodes of thrombus embolization.31,32 In patients with intermittent symptoms, an increasingFocal myocardial necrosis was shown to be surrounded by number of episodes preceding the index event may alsoareas of inflammation.44 In clinical practice, this minor have an impact on outcome. The presence of tachycardia,damage may be detected only by cardiac troponin T hypotension, or heart failure upon presentation indicates a(cTnT) or troponin I (cTnI) elevations and are classified as poor prognosis and needs rapid diagnosis and management.MI according to the ESC/AHA/ACC Consensus Document.5 It is important to identify clinical circumstances that mayThis concept is of clinical importance, because it has exacerbate or precipitate NSTE-ACS, such as anaemia, infec-major practical implications with respect to short-term tion, inflammation, fever, and metabolic or endocrine (inprognosis and the choice of the therapeutic regimen. particular thyroid) disorders. A classification of unstable angina was introduced by Braunwald50 and was based on the severity of pain, the cir- cumstances under which it occurs, and precipitating factors4. Diagnosis and risk assessment associated with its onset, and was later validated as a prog-Diagnosis and risk stratification are closely linked in ACS. nostic tool.51 However, its usefulness in the clinical setting isDuring the process of establishing the diagnosis of ACS and limited to the finding that patients with pain at rest duringexcluding differential diagnoses, the risk is repeatedly the last 48 h are at increased risk, particularly if troponinsassessed and serves as a guide for the therapeutic manage- are elevated.52ment. Patients with NSTE-ACS are at high risk for MI, recur- When faced with a symptomatic patient, there are severalrence of MI, or death. Risk must not be understood in a clinical findings that increase the probability of a diagnosisbinary way, but rather as a continuum from patients with of CAD and therefore NSTE-ACS. These include older age,very high risk to patients with low risk. male gender, and known atherosclerosis in non-coronary
  7. 7. 1604 ESC Guidelinesterritories, such as peripheral or carotid artery disease. The R-waves, who in turn have a higher risk than those withpresence of risk factors, in particular diabetes mellitus and a normal ECG on admission. Some studies have cast doubtrenal insufficiency as well as prior manifestation of CAD, i.e. on the prognostic value of isolated T-wave inversion.previous MI, percutaneous coronary intervention (PCI), or However, deep symmetrical inversion of the T-waves in thecoronary bypass graft surgery (CABG), also raises the likeli- anterior chest leads is often related to a significant stenosishood of NSTE-ACS. However, all of these factors are not of the proximal left anterior descending coronary artery orspecific, so that their diagnostic value should not be main stem.59overestimated. It should be appreciated that a completely normal ECG does not exclude the possibility of NSTE-ACS. In several4.2 Diagnostic tools studies, around 5% of patients with normal ECG who were discharged from the emergency department were ultimately4.2.1 Physical examination found to have either an acute MI or an unstable angina.60,61The physical examination is frequently normal. Signs of Particularly, ischaemia in the territory of the circumflexheart failure or haemodynamic instability must prompt the artery frequently escapes the common 12-lead ECG, butphysician to expedite the diagnosis and treatment of may be detected in lead V4R and V3R as well as in leadspatients. An important goal of the physical examination is V7–V9. Transient episodes of bundle branch block occasion-to exclude non-cardiac causes of chest pain and non- ally occur during ischaemic attacks.ischaemic cardiac disorders (e.g. pulmonary embolism,aortic dissection, pericarditis, valvular heart disease), or Continuous ST-segment monitoringpotentially extra-cardiac causes, such as acute pulmonary The standard ECG at rest does not adequately reflect thediseases (e.g. pneumothorax, pneumonia, pleural effusion). dynamic nature of coronary thrombosis and myocardialIn this regard, differences in blood pressure between the ischaemia. Almost two-thirds of all ischaemic episodes inupper and lower limbs, an irregular pulse, heart murmurs, the phase of instability are clinically silent and, hence, nota friction rub, pain on palpation, and abdominal masses likely to be detected by conventional ECG. On-line continu-are physical findings that may suggest a diagnosis other ous computer-assisted 12-lead ST-segment monitoring is athan NSTE-ACS. Other physical findings such as palor, valuable diagnostic tool. Several studies revealed that 15–increased sweating, or tremor may orientate towards preci- 30% of patients with NSTE-ACS have transient episodes ofpitating conditions, such as anaemia and thyrotoxicosis. ST-segment changes, predominantly ST-segment depression. These patients have an increased risk of subsequent cardiac4.2.2 Electrocardiogram events. ST-monitoring adds independent prognostic infor-The resting 12-lead ECG is the first-line diagnostic tool in mation to the ECG at rest, troponins, and other clinicalthe assessment of patients with suspected NSTE-ACS. It parameters.62–65should be obtained within 10 min after first medical Exercise or other stress testingcontact upon arrival of the patient in the emergency In patients who continue to have typical ischaemic chestroom and immediately interpreted by a qualified phys- pain, no stress test should be performed. However, a stressician.53 The finding of persistent (.20 min) ST-elevation test has a predictive value and is therefore useful before dis-suggests STEMI which requires different treatment.2 In charge in patients with non-diagnostic ECG provided there isthe absence of ST-elevation, additional recordings should no pain, no signs of heart failure, and normal biomarkersbe obtained when the patient is symptomatic and com- (repeat testing). Early exercise testing has a high negativepared with recordings obtained in an asymptomatic state. predictive value. Parameters reflecting cardiac performanceComparison with a previous ECG, if available, is valuable, provide at least as much prognostic information as thoseparticularly in patients with co-existing cardiac disorders reflecting ischaemia, while the combination of these par-such as LV hypertrophy or a previous MI. ECG recordings ameters gives the best prognostic information.66should be repeated at least at 6 and 24 h, and in the caseof recurrence of chest pain/symptoms. A pre-discharge 4.2.3 Biochemical markersECG is advisable. Several biomarkers have been investigated in recent years ST-segment shifts and T-wave changes are the ECG indi- to be used for diagnostic and risk stratification. Thesecators of unstable CAD.21,54 The number of leads showing reflect different pathophysiological aspects of NSTE-ACS,ST-depression and the magnitude of ST-depression are such as minor myocardial cell injury, inflammation, plateletindicative of the extent and severity of ischaemia and corre- activation, or neurohormonal activation. For the long-termlate with prognosis.55 ST-segment depression !0.5 mm prognosis, indicators of LV and renal dysfunction or diabetes(0.05 mV) in two or more contiguous leads, in the appropri- also play an important role.ate clinical context, is suggestive of NSTE-ACS and linked toprognosis.56 Minor (0.5 mm) ST-depression may be difficult Markers of myocardial injuryto measure in clinical practice. More relevant is cTnT or cTnI are the preferred markers of myocardial injury,ST-depression of !1 mm (0.1 mV) which is associated with because they are more specific and more sensitive than thean 11% rate of death and MI at 1 year.54 ST-depression of traditional cardiac enzymes such as creatinine kinase (CK) or!2 mm carries about a six-fold increased mortality risk.57 its isoenzyme MB (CK-MB). In this setting, myoglobin is notST-depression combined with transient ST-elevation also specific and sensitive enough to allow the detection of myo-identifies a high-risk subgroup.58 cardial cell injury and therefore not recommended for Patients with ST-depression have a higher risk for sub- routine diagnosis and risk stratification.67sequent cardiac events compared with those with isolated It is believed that the elevation of cardiac troponinsT-wave inversion (.1 mm) in leads with predominant reflects irreversible myocardial cellular necrosis typically
  8. 8. ESC Guidelines 1605 Table 3 Non-coronary conditions with troponin elevations68 Severe congestive heart failure: acute and chronic Aortic dissection, aortic valve disease, or hypertrophic cardiomyopathy Cardiac contusion, ablation, pacing, cardioversion, or endomyocardial biopsy Inflammatory diseases, e.g. myocarditis, or myocardial extension of endocarditis/pericarditis Hypertensive crisis Tachy- or bradyarrhythmias Pulmonary embolism, severe pulmonary hypertension Hypothyroidism Apical ballooning syndrome Chronic or acute renal dysfunctionFigure 2 Example of release of cardiac markers in a patient with Acute neurological disease, including stroke, or subarachnoidnon-ST-elevation acute coronary syndrome (shaded area indicates normal haemorrhagerange). Infiltrative diseases, e.g. amyloidosis, haemochromatosis, sarcoidosis, scleroderma Drug toxicity, e.g. adriamycin, 5-fluorouracil, herceptin, snake venomsresulting from distal embolization of platelet-rich thrombi Burns, if affecting .30% of body surface area Rhabdomyolysisfrom the site of a ruptured plaque. Accordingly, troponins Critically ill patients, especially with respiratory failure, or sepsismay be seen as a surrogate marker of active thrombus for-mation. In the setting of myocardial ischaemia (chest pain,ST-segment changes) troponin elevation has to be labelledas MI according to the ESC/ACC/AHA Consensus Document5currently under revision.68 differential diagnosis. Elevation of cardiac troponins also Troponins are the best biomarker to predict short-term occurs in the setting of non-coronary-related myocardial(30 days) outcome with respect to MI and death.69–72 The injury (Table 3). This reflects the sensitivity of the markerprognostic value of troponin measurements has also been for myocardial cell injury and should not be labelledconfirmed for the long term (1 year and beyond). The as false-positive test results. True ‘false-positive’ resultsincreased risk associated with elevated troponin levels is have been documented in the setting of skeletal myopathiesindependent of and additive to other risk factors such or chronic renal failure. Elevation of troponins is fre-as ECG changes at rest or on continuous monitoring, or quently found when serum creatinine level is .2.5 mg/dLmarkers of inflammatory activity.52,71 Furthermore, the (221 mmol/L) in the absence of proven ACS, and is alsoidentification of patients with elevated troponins levels is associated with adverse prognosis.77,78 Troponin elevationsalso useful for selecting appropriate treatment in patients that cannot be explained are rare.with NSTE-ACS.73–75 There is no fundamental difference between troponin T In patients with MI, an initial rise in troponins in periph- and troponin I. Differences between study results areeral blood occurs after 3–4 h. Troponin levels may persist predominantly explained by varying inclusion criteria,elevated for up to 2 weeks caused by proteolysis of the con- differences in sampling patterns, and the use of assaystractile apparatus. In NSTE-ACS, minor elevation of tropo- with different diagnostic cut-offs. The diagnostic cut-offnins may be measurable only over 48–72 h (Figure 2). The for MI using cardiac troponins should be based on thehigh sensitivity of troponin tests allows the detection of 99th percentile of levels among healthy controls as rec-myocardial damage undetected by CK-MB in up to one-third ommended by the Consensus committee. Acceptableof patients presenting with NSTE-ACS. Minor or moderate imprecision (coefficient of variation) at the 99th percentileelevations of troponins appear to carry the highest early for each assay should be 10%.5 Each individual laboratoryrisk in patients with NSTE-ACS.72 should regularly assess the range of reference values in A single negative test for troponins on arrival of the patient their specific setting.in hospital is not sufficient for ruling out an elevation, as in The diagnosis of NSTE-ACS should never be made only onmany patients an increase in troponins can be detected the basis of cardiac biomarkers, whose elevation should beonly in the subsequent hours. In order to demonstrate or to interpreted in the context of other clinical findings.exclude myocardial damage, repeated blood sampling andmeasurements are required 6–12 h after admission andafter any further episodes of severe chest pain.76 A second Markers of inflammatory activitysample in the absence of any other suspicious findings may Of the numerous inflammatory markers that have beenbe omitted only if the patient’s last episode of chest pain investigated over the past decade, C-reactive proteinwas more than 12 h prior to the initial determination of measured by high-sensitive (hsCRP) assays is the mosttroponins. widely studied and linked to higher rates of adverse It is important to stress that other life-threatening con- events. The exact source of elevated hsCRP levels amongditions presenting with chest pain, such as dissecting patients with NSTE-ACS remains unclear. Given that myocar-aortic aneurysm or pulmonary embolism, may also result in dial damage is also a major inflammatory stimulus, an acuteelevated troponins and should always be considered as a inflammatory process induced by myocardial damage is
  9. 9. 1606 ESC Guidelinessuperimposed on a chronic inflammatory condition, both of Novel biomarkerswhich might influence long-term outcome in NSTE-ACS. A considerable number of patients can still not be identified There is robust evidence that even among patients as being at high risk by today’s routine biomarkers. Accord-with troponin-negative NSTE-ACS, elevated levels of ingly, a great number of novel biomarkers have been investi-hsCRP are predictive of long-term mortality gated in recent years to explore their usefulness as(.6 months).37,71,79,80 The FRISC study confirmed that diagnostic tools and for risk stratification in addition tomortality is associated with elevated hsCRP levels at the established markers. Several novel biomarkers have beentime of the index event and continues to increase over studied. These include markers of oxidative stress (myeloper-4 years.36 This was also observed in large cohorts of oxidase),96,97 markers of thrombosis and inflammation (e.g.patients submitted to planned PCI.81 However, hsCRP has soluble CD40 ligand),98,99 or markers involved more upstreamno role for the diagnosis of ACS. in the inflammation cascade, i.e. markers specific of vascular inflammation. All have shown their incremental value overMarkers of neurohumoral activation troponins in retrospective analyses, but have not beenNeurohumoral activation of the heart can be monitored by tested prospectively and are not yet available for routine use.measurements of systemic levels of natriuretic peptides Multimarker approachsecreted from the heart. Natriuretic peptides, such as brain- Since NSTE-ACS is a complex event, several markers reflect-type [B-type natriuretic peptide (BNP)] or its N-terminal ing the respective pathophysiological pathways may beprohormone fragment (NT-proBNP), are highly sensitive advantageous for risk stratification. It is useful to distinguishand fairly specific markers for the detection of LV dysfunc- between markers for the acute risk of MI and for long-termtion. There are robust retrospective data in NSTE-ACS mortality. The combined use of markers for myocardialshowing that patients with elevated BNP or NT-proBNP necrosis, inflammation, myocardial and renal dysfunction,levels have a three- to five-fold increased mortality rate and neurohumoral activation may significantly add to ourwhen compared with those with lower levels.82,83 The ability to identify correctly patients who are at high risklevel is strongly associated with the risk of death even for future cardiovascular events. Several studies demon-when adjusted for age, Killip class, and LV ejection fraction strated that a multimarker approach improves risk(EF).71 Values taken a few days after onset of symptoms stratification.71,79,98seem to have superior predictive value when compared Currently, it is recommended to use troponins (cTnT orwith measurements on admission.84,85 Natriuretic peptides cTnI) for the acute risk stratification on arrival of theare useful markers in the emergency room in evaluating patient in the hospital. At the same time or during the sub-chest pain or dyspnoea and were shown to be helpful in dif- sequent days, CrCl and BNP or NT-pro-BNP allow estimationferentiating between cardiac and non-cardiac causes of dys- of any renal or myocardial dysfunction with its inherentpnoea. However, they are markers of long-term prognosis, impacts on treatment and long-term outcome. Currently,but have limited value for initial risk stratification and only hsCRP is available on a routine basis for the detectionhence for selecting the initial therapeutic strategy in of the underlying inflammatory activity responsible for long-NSTE-ACS.86 term mortality.Markers of renal function Point-of-care (bedside) biomarker testingImpaired renal function is a strong independent predictor The diagnosis of NSTE-ACS and the assignment to a risk groupfor long-term mortality in ACS patients.71,87,88 Serum creati- should be undertaken as rapidly as possible (see section 8nine concentration is a less reliable indicator of renal func- Management strategies). Point-of-care testing for biochemi-tion than creatinine clearance (CrCl) or glomerular filtration cal markers is advantageous to establish diagnosis. Theserate (GFR), because it is affected by a multitude of factors, tests can be performed either directly at the bedside or atincluding age, weight, muscle mass, race, and various medi- ‘near patient’ locations such as the emergency department,cations.89 Several formulae have been devised to improve chest pain evaluation centre, or intensive care unit.76,100,101the accuracy of serum creatinine level as a surrogate of Point-of-care tests for troponins should be implementedGFR, including the Cockcroft–Gault90 and the abbreviated when a central laboratory cannot consistently provide testModification of Diet in Renal Disease (MDRD) equations.91 results within 60 min.102 No special skill or prolonged train-Long-term mortality is influenced by the degree of renal ing is required to read the result of these assays. Accord-function, as it increases exponentially with decreasing ingly, these tests can be performed by various members ofGFR/CrCl. When compared with patients with normal renal the health-care team after adequate training.103 However,function, the odds ratio (OR) for death at 1 year was 1.76 reading of these mostly qualitative tests is performed visu-for mild renal dysfunction, 2.72 for moderate renal dysfunc- ally and therefore is observer-dependent. Some companiestion, and 6.18 for severe renal dysfunction.88 (see section provide optical reading devices for the emergency room7.4 Chronic kidney disease). setting.104 The tests are usually reliable when positive. Cystatin C is considered to be a surrogate marker of renal However, in the presence of a remaining suspicion offunction superior to CrCl or GFR estimation.93,94 Cystatin C is unstable CAD, negative tests should be repeated at a latera cysteine proteinase inhibitor produced by all nucleated time point and verified by a central laboratory.cells at a constant rate and excreted into the bloodstream.Because of its low molecular weight (13 kDa), it is freely 4.2.4 Echocardiography and non-invasivefiltered at the glomerulus and is almost completely reab- myocardial imagingsorbed and catabolized, but not secreted, by tubular cells. LV systolic function is an important prognostic variable inCystatin C levels have been shown to be good markers of patients with ischaemic heart disease and can be easilyprognosis,95 although not widely available yet. and accurately assessed by echocardiography. In
  10. 10. ESC Guidelines 1607experienced hands, transient localized hypokinesia or akine- differential diagnoses, such as pulmonary embolism orsia in segments of the left ventricle wall may be detected aortic dissection.during ischaemia, with normal wall motion on resolutionof ischaemia. Furthermore, differential diagnoses such asaortic stenosis, aortic dissection, pulmonary embolism, orhypertrophic cardiomyopathy may be identified.105 There- 4.3 Differential diagnosesfore, echocardiography should routinely be used in emer-gency units. There are several cardiac and non-cardiac conditions that Stress echocardiography is helpful in stabilized patients to may mimic NSTE-ACS (Table 4).obtain objective evidence of ischaemia and has the same Underlying chronic heart conditions such as hypertrophicindications as other exercise modalities.106 Similarly, stress cardiomyopathy and valvular heart disease (i.e. aortic ste-scintigraphy107,108 or magnetic resonance imaging (MRI)109 nosis, aortic regurgitation) may be associated with typicalmay be used, if available. MRI is useful to assess myocardial symptoms of NSTE-ACS, elevated cardiac biomarkers, andviability. Rest myocardial scintigraphy was shown to be ECG changes.113 Since some patients with these underlyinghelpful for initial triage of patients presenting with chest conditions also have CAD, the diagnostic process can bepain without ECG changes or evidence of ongoing MI.110 difficult. Myocarditis, pericarditis, or myopericarditis of different aetiologies may be associated with chest pain that resembles the typical angina of NSTE-ACS and be associated with a4.2.5 Imaging of the coronary anatomy rise in cardiac biomarker levels, ECG changes, and wallImaging modalities provide unique information on the pre- motion abnormalities. A flu-like, febrile condition withsence and the severity of CAD. The gold standard is still symptoms attributed to the upper respiratory tract oftenconventional invasive coronary angiography. precedes or accompanies these conditions. However, infec- Patients with multiple vessel disease as well as those with tions, especially of the upper respiratory tract, also oftenleft main stenosis are at the highest risk of serious cardiac precede or accompany NSTE-ACS.114 The definitive diagnosisevents.111 Angiographic assessment of the characteristics of myocarditis or myopericarditis may frequently only beand location of the culprit lesion as well as other lesions is established during the course of hospitalization.essential if revascularization is being considered. Complex, Non-cardiac, life-threatening conditions may mimiclong, heavily calcified lesions, angulations and extreme tor- NSTE-ACS and must be diagnosed. Among these, pulmonarytuosity of the vessel are indicators of risk. Highest risk is embolism may be associated with dyspnoea, chest pain,associated with the occurrence of filling defects indicating ECG changes, as well as elevated levels of cardiac bio-intracoronary thrombus formation. markers similar to those of NSTE-ACS.115 Chest X-ray, CT, At the current state of development, cardiac computed or MRI angiography of the pulmonary arteries, pulmonarytomography (CT) cannot be recommended as the coronary perfusion scans, and blood levels of D-dimer are the rec-imaging modality in NSTE-ACS, because of suboptimal diag- ommended diagnostic tests. Aortic dissection is another con-nostic accuracy. Fast technical evolution may result in dition to be considered as an important differentialimproved diagnostic accuracy in the near future and lead diagnosis. NSTE-ACS may be a complication of aortic dissec-to reconsideration of the use of this tool in the decision- tion when the dissection involves the coronary arteries. In amaking process.112 Furthermore, because of the high likeli- patient with undiagnosed aortic dissection, the currenthood of PCI, time is lost and the patient is exposed to therapies for NSTE-ACS may exacerbate the patient’s con-unnecessary radiation and contrast medium utilization if dition and result in detrimental outcomes. Stroke may beCT is used as the first diagnostic option. accompanied by ECG changes, wall motion abnormalities, MRI is not established as an imaging tool for coronary and a rise in cardiac biomarker levels.116 Conversely, atypi-arteries. It may only be useful in the course of hospitalization cal symptoms such as headache and vertigo may in rarein quantifying myocardial injury or excluding myocarditis.109 cases be the sole presentation of myocardial ischaemia.CT or MRI may, however, be indicated for evaluation of Table 4 Cardiac and non-cardiac conditions that can mimic non-ST-elevation acute coronary syndromes Cardiac Pulmonary Haematological Vascular Gastrointestinal Orthopaedic Myocarditis Pulmonary Sickle cell Aortic dissection Oesophageal Cervical discopathy embolism anaemia spasm Pericarditis Pulmonary Aortic aneurysm Oesophagitis Rib fracture infarction Myopericarditis Pneumonia Aortic coarctation Peptic ulcer Muscle injury/ Pleuritis inflammation Cardiomyopathy Pneumothorax Cerebrovascular Pancreatitis Costochondritis disease Valvular disease Cholescystitis Apical ballooning (Tako-Tsubo syndrome)
  11. 11. 1608 ESC Guidelines4.4 Risk scores separate risk stratification of patients with unstable angina and NSTE-MI. It is a complex model with high discriminativeSeveral risk stratification scores have been developed and power, but poor calibration in the Canadian ACS Registry.validated in large patient populations. In clinical practice,only simple risk scores are useful. Recommendations for diagnosis and risk stratification The GRACE risk scores8,117,118 are based upon a large † Diagnosis and short-term risk stratification of NSTE-ACSunselected population of an international registry of the should be based on a combination of clinical history,full spectrum of ACS patients. The risk factors were symptoms, ECG, biomarkers, and risk score results (I-B).derived with independent predictive power for in-hospital † The evaluation of the individual risk is a dynamic processdeaths118 and post-discharge deaths at 6 months.8 Easy to that is to be updated as the clinical situation evolves.assess clinical/ECG/laboratory variables such as age, heartrate, systolic blood pressure, serum creatinine level, Killip † A 12-lead ECG should be obtained within 10 min afterclass at admission, presence of ST-depression, and elevated first medical contact and immediately read by ancardiac biomarkers as well as cardiac arrest are included in experienced physician (I-C). Additional leads (V3Rthe calculation. The models were validated in GRACE and and V4R, V7–V9) should be recorded. ECG should beGUSTO-2B, as well as externally in a Mayo Clinic population, repeated in the case of recurrence of symptoms,a Canadian ACS Registry, and a Portuguese Registry. The and at 6 and 24 h and before hospital discharge (I-C).GRACE models have very good discriminative power. Their † Blood must be drawn promptly for troponin (cTnT orcomplexity, however, requires special tools (graphs, tables, cTnI) measurement. The result should be availableor computer programs) to estimate risk at the bedside. Com- within 60 min (I-C). The test should be repeatedputer or PDA software of a simplified nomogram are freely after 6–12 h if the initial test is negative (I-A).available at http://www.outcomes.org/grace. According to † Established risk scores (such as GRACE) should bethe GRACE risk score, three risk categories have been devel- implemented for initial and subsequent risk assess-oped (Table 5). On the basis of direct comparisons,119 the ment (I-B).GRACE risk score is recommended as the preferred classifi- † An echocardiogram is recommended to rule in/outcation to apply on admission and at discharge in daily clinical differential diagnoses (I-C).routine practice. † In patients without recurrence of pain, normal ECG The TIMI risk score120 is derived from the TIMI-11B trial findings, and negative troponins tests, a non-invasivepopulation and was validated in the TIMI-11B and ESSENCE stress test for inducible ischaemia is recommendedpatients, as well as externally such as in a Mayo Clinic popu- before discharge (I-A).lation, in the TIMI-3 and Portuguese Registries. The TIMI risk † The following predictors of long-term death or MIscore was applied in analysing treatment efficacy in various should be considered in risk stratification (I-B).risk groups. It is less accurate in predicting events, but itssimplicity makes it useful and widely accepted. The FRISC † Clinical indicators: age, heart rate, blood pressure,score is based on similar variables and was derived from Killip class, diabetes, previous MI/CAD;the 1-year outcome of the FRISC-2 trial.121 This is the only † ECG markers: ST-segment depression;risk score that has repeatedly been shown to identify † Laboratory markers: troponins, GFR/CrCl/cystatin C,patients with a long-term benefit of an early invasive treat- BNP/NT-proBNP, hsCRP;ment strategy in a randomized trial.122 The PURSUIT risk † Imaging findings: low EF, main stem lesion, three-score is based upon the PURSUIT trial population and was vessel disease;validated externally in the Canadian ACS Registry, a Mayo † Risk score result.Clinic population, and in a Portuguese Registry.123 It allows 5. Treatment The treatment options described in this section are based on evidence from numerous clinical trials or meta-analyses. Table 5 Mortality in hospital and at 6 months in low-, Four categories of acute treatment are discussed: anti- intermediate-, and high-risk categories in registry populations ischaemic agents, anticoagulants, antiplatelet agents, and cor- according to the GRACE risk score8,117 onary revascularization. Generally, the therapeutic approach is based on whether the patient is to be only medically treated, or Risk category GRACE risk In-hospital deaths (%) in addition referred to angiography and revascularization. (tertiles) score Many of the treatment options were evaluated more than two decades ago or tested only in specific subsets of patients. Low 108 ,1 The recommendations take these circumstances into account. Intermediate 109–140 1–3 High .140 .3 5.1 Anti-ischaemic agents Risk category GRACE risk Post-discharge to 6 months (tertiles) score deaths (%) These drugs decrease myocardial oxygen consumption (decreasing heart rate, lowering blood pressure, or Low 88 ,3 depressing LV contractility) and/or induce vasodilatation. Intermediate 89–118 3–8 High .118 .8 5.1.1 Beta-blockers For calculations, see http://www.outcomes.org/grace. Evidence for the beneficial effects of beta-blockers in unstable angina is based on limited randomized trial data, along with
  12. 12. ESC Guidelines 1609pathophysiological considerations and extrapolation from conduction and heart rate. There are three subclasses ofexperience in stable angina and STEMI. Beta-blockers compe- calcium blockers, which are chemically distinct and havetitively inhibit the myocardial effects of circulating catechol- different pharmacological effects: the dihydropyridinesamines. In NSTE-ACS, the primary benefits of beta-blockers (such as nifedipine), the benzothiazepines (such as diltia-are related to their effects on beta-1 receptors that result in zem), and the phenylalkylamines (such as verapamil). Thea decrease in myocardial oxygen consumption. agents in each subclass vary in the degree to which they Two double-blind, randomized trials have compared beta- cause vasodilatation, decrease myocardial contractility,blockers with placebo in unstable angina.124,125 A meta- and delay atrioventricular (A-V) conduction. A-V block mayanalysis suggested that beta-blocker treatment was associ- be induced by non-dihydropyridines. Nifedipine and amlodi-ated with a 13% relative reduction in risk of progression to pine produce the most marked peripheral arterial vasodila-STEMI.126 Although no significant effect on mortality in tation, whereas diltiazem has the least vasodilatoryNSTE-ACS has been demonstrated in these relatively small effect. All subclasses cause similar coronary vasodilatation.trials, the results may be extrapolated from larger randomized There are only small randomized trials testing calciumtrials of beta-blockers in patients with unselected MI.127 channel blockers in NSTE-ACS. Generally, they show efficacy Beta-blockers are recommended in NSTE-ACS in the in relieving symptoms that appear equivalent to beta-absence of contraindications and are usually well tolerated. blockers.133,134 The HINT study, the largest randomizedIn most cases, oral treatment is sufficient. The target heart trial, tested nifedipine and metoprolol in a 2Â2 factorialrate for a good treatment effect should be between 50 and design.125 Although no statistically significant differences60 b.p.m. Patients with significantly impaired atrioventricu- were observed, there was a trend towards an increasedlar conduction and a history of asthma or of acute LV risk of MI or recurrent angina with nifedipine (compareddysfunction should not receive beta-blockers. with placebo), whereas treatment with metoprolol, or with a combination of both drugs, was associated with a5.1.2 Nitrates reduction in these events.The use of nitrates in unstable angina is largely based on The beneficial effect after discharge is somewhat contro-pathophysiological considerations and clinical experience. versial.135,136 A meta-analysis of the effects of calciumThe therapeutic benefits of nitrates and similar drug channel blockers on death or non-fatal MI in unstable anginaclasses such as sydnonimines are related to their effects suggests that this class of drugs does not prevent the develop-on the peripheral and coronary circulation. The major thera- ment of acute MI or reduce mortality.137 In particular, severalpeutic benefit is probably related to the venodilator effects analyses of pooled data from observational studies suggestthat lead to a decrease in myocardial pre-load and LV end- that short-acting nifedipine might be associated with a dose-diastolic volume, resulting in a decrease in myocardial dependent detrimental effect on mortality in patients withoxygen consumption. In addition, nitrates dilate normal as CAD.138,139 On the other hand, there is evidence for a protec-well as atherosclerotic coronary arteries and increase coron- tive role of diltiazem in NSTEMI in one trial.140ary collateral flow. Calcium channel blockers, particularly dihydropyridines, Studies of nitrates in unstable angina have been small and are the drugs of choice in vasospastic angina.observational.128–130 There are no randomized placebo-controlled trials to confirm the benefits of this class ofdrugs either in relieving symptoms or in reducing major 5.1.4 New drugsadverse cardiac events. Only very scarce data exist about New antianginal drugs with different modes of action havethe best route for administrating nitrates (intravenous, been investigated in recent years. Ivabradine selectively inhi-oral, sublingual, or topical) and about the optimal dose bits the primary pacemaker current in the sinus node andand duration of therapy.131,132 may be used in patients with beta-blocker contraindica- In patients with NSTE-ACS who require hospital admission, tions.141 Trimetazidine exerts metabolic effects withoutintravenous nitrates may be considered in the absence haemodynamic changes.142 Ranolazine exerts antianginalof contraindications. The dose should be titrated upwards effects by inhibiting the late sodium current.143 It wasuntil symptoms (angina and/or dyspnoea) are relieved not effective in reducing major cardiovascular events inunless side effects (notably headache or hypotension) MERLIN-TIMI 36.92 Nicorandil has nitrate-like properties.occur. A limitation of continuous nitrate therapy is the Nicorandil significantly reduced the rate of occurrence ofphenomenon of tolerance, which is related to both the the primary composite endpoint (coronary death, non-fataldose administered and the duration of treatment. When MI, or unplanned hospital admission for cardiac pain) insymptoms are controlled, intravenous nitrates may be chronic stable angina patients in the IONA study,144 but hasreplaced by non-parenteral alternatives with appropriate never been tested in the setting of NSTE-ACS.nitrate-free intervals. An alternative is to use nitrate-likedrugs such as sydnonimines or potassium channel activators. Recommendations for anti-ischaemic drugsNitric oxide donor therapy (nitrates and sydnonimines) is † Beta-blockers are recommended in the absence of con-contraindicated in patients taking phosphodiesterase-5 traindications, particularly in patients with hyperten-inhibitors (sildenafil, vardenafil, tadalafil) because of the sion or tachycardia (I-B).risk of profound vasodilatation and blood pressure drop in † Intravenous or oral nitrates are effective for symptomthe case of concomitant administration. relief in the acute management of anginal episodes (I-C).5.1.3 Calcium channel blockers † Calcium channel blockers provide symptom relief inCalcium channel blockers are vasodilating drugs. In addition, patients already receiving nitrates and beta-blockers;some have significant direct effects on atrioventricular they are useful in patients with contraindications to
  13. 13. 1610 ESC Guidelines beta-blockade and in the subgroup of patients with of recurrence, despite simultaneous acetylsalicylic acid vasospastic angina (I-B). (aspirin) treatment.147† Nifedipine, or other dihydropyridines, should not be used unless combined with beta-blockers (III-B). Treatment effects A pooled analysis of six trials testing short-term UFH vs. placebo or untreated controls showed a significant risk5.2 Anticoagulants reduction for death and MI of 33% (OR 0.67, 95% CI 0.45–Anticoagulants are used in the treatment of NSTE-ACS to 0.99, P ¼ 0.045).148 The risk reduction for MI accountedinhibit thrombin generation and/or activity, thereby redu- for practically all of the beneficial effect. When the datacing thrombus-related events. There is clear evidence that from FRISC, which compared LMWH with placebo, are addedanticoagulation is effective in addition to platelet inhibition to this pooled analysis, the risk reduction is even greaterand that the combination of the two is more effective than (Figure 3). In trials comparing the combination of UFH pluseither treatment alone.145,146 With all anticoagulants, there aspirin vs. aspirin alone in NSTE-ACS, a trend towards ais an increased risk of bleeding. The risk factors for bleeding benefit was observed in favour of the UFH–aspirin combi-are well defined (see section 6.1 Bleeding complications). nation, but at the cost of an increase in the risk of bleeding.Several anticoagulants, which act at different levels of the Recurrence of events after interruption of UFH explains whycoagulation cascade, have been investigated in NSTE-ACS: this benefit is not maintained over time, unless the patient is revascularized before the interruption of UFH148–150 (Figure 3).† unfractionated heparin (UFH) as intravenous infusion;† low molecular weight heparin (LMWH) as subcutaneous injection; 5.2.2 Low molecular weight heparin† fondaparinux as subcutaneous injection; Pharmacology† direct thrombin inhibitors (DTIs) as intravenous infusion; LMWH represents a class of heparin-derived compounds with† vitamin K antagonists (VKAs) as oral medication. molecular weights ranging from 2000 to 10 000 Da. LMWHs have pharmacological advantages over UFH. They link to antithrombin through the pentasaccharide sequence. This5.2.1 Unfractionated heparin is the basis of anti-Xa activity. The anti-IIa activity is lowerPharmacology than that with UFH and depends on the molecular weightUFH is a heterogeneous mixture of polysaccharide molecu- of the molecule, with greater anti-IIa activity with increas-les, with a molecular weight ranging from 2000 to 30 000 ing molecular weight. The advantages of LMWH are an(mostly 15–18 000) Da. One-third of the molecules found almost complete absorption after subcutaneous adminis-within a standard UFH preparation contain the pentasac- tration, less protein binding, less platelet activation, and,charide sequence, which binds to antithrombin and acceler- thereby, a more predictable dose–effect relationship.145,146ates the rate at which antithrombin inhibits factor-Xa. Furthermore, there is a lower risk of heparin-induced throm-Inhibition of factor-IIa requires heparin to bind to both bocytopenia (HIT) with LMWH when compared with UFH duethrombin and antithrombin to bridge them. This can only to less interaction with platelet factor 4 (PF4) (see sectionbe achieved if the chains containing the pentasaccharide 6.2 Thrombocytopenia). LMWHs are eliminated at leastsequence comprise at least 18 saccharide units to provide partially by the renal route. They are contraindicated insufficient length to bridge to factor-IIa. UFH is poorly the case of renal failure with CrCl ,30 mL/min (in certainabsorbed by the subcutaneous route, so that intravenous countries such as the USA, dose adaptation in the case ofinfusion is the preferred route of administration. The thera- renal failure is recommended; see section 7.4 Chronicpeutic window is narrow, requiring frequent monitoring of kidney disease).the activated partial thromboplastin time (aPTT), with an The LMWH dosages used in NSTE-ACS are body weightoptimal target level of 50–75 s, corresponding to 1.5–2.5 adjusted and are of the same magnitude as those used intimes the upper limit of normal. At higher aPTT values, the treatment of venous thrombo-embolism (VTE), whichthe risk of bleeding complications is increased, without are higher than the doses used in prophylaxis of deep veinfurther antithrombotic benefits. At aPTT values lower than thrombosis (DVT). LMWHs are commonly administered sub-50 s, the antithrombotic effect is limited and the number cutaneously every 12 h in NSTE-ACS to avoid the risk ofof ischaemic events not reduced. A weight-adjusted dose inadequate anti-Xa level during treatment.149,151–155 Anof UFH is recommended, at an initial bolus of 60–70 IU/kg initial intravenous bolus in high-risk patients has also beenwith a maximum of 5000 IU, followed by an infusion of 12– advocated.151 From VTE studies, the therapeutic range of15 IU/kg/h, to a maximum of 1000 IU/h. This regimen is anti-Xa activity has been considered to be 0.6–1.0 IU/mL,that currently recommended as being the most likely to without any clear relationship between anti-Xa activityachieve the target aPTT values.145,146 and clinical outcome. However, the bleeding risk increases The maintenance of a well-controlled anticoagulation is above 1.0 IU/mL of anti-Xa activity.145,146 In TIMI-11A,difficult by UFH infusion in NSTE-ACS patients, especially where the enoxaparin dose was 1.5 mg/kg twice daily,as the clinical condition usually improves within the first patients with major haemorrhage had anti-Xa activity24 h, when the patients often are mobilized and even ambu- in the range of 1.8–2.0 IU/mL. Excess bleeding led to alatory. The anticoagulant effect of UFH is rapidly lost within reduction in the dosage.156 With the current doses used ina few hours after interruption. During the first 24 h after ter- clinical practice, monitoring of anti-Xa activity is notmination of treatment, there is a risk of reactivation of the necessary, except in special populations of patients, suchcoagulation process and thereby a transiently increased risk as those with renal failure and obesity.

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