CPG Management of NSTE-ACS 3rd Edition 2021 PDF

E D I T I O N 2021 IDELINES RD 3 C T IC E G U CLINIC A L P R A MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS)*...

E D I T I O N 2021 IDELINES RD 3 C T IC E G U CLINIC A L P R A MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS)* * This is a combination of Unstable Angina and Non ST Elevation Myocardial Infarction (UA/NSTEMI) PUBLISHED BY: National Heart Association of Malaysia D-13A-06, Menara SUEZCAP 1, KL Gateway No.2 Jalan Kerinchi, Gerbang Kerinchi Lestari 59200 Kuala Lumpur e ISBN 978-967-11794-6-8 COPYRIGHT The owners of this publication are the National Heart Association of Malaysia (NHAM) and the Academy of Medicine Malaysia. The content in this document may be produced in any number of copies and in any format or medium provided that a copyright acknowledgement to the owners is included and the content is not changed in any form or method, not sold and not used to promote or endorse any product or service. In addition, the content is not to be used in any inappropriate or misleading context. © 2021 National Heart Association of Malaysia. All right reserved. CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 STATEMENT OF INTENT This Guidelines was developed to be a guide for best clinical practice in the management of Non- ST Elevation Acute Coronary Syndrome (NSTE-ACS). This is a combination of both Unstable Angina (UA) and Non-ST Elevation Myocardial Infarction (NSTEMI). It is based on the best evidence currently available. Adherence to this Guidelines does not necessarily lead to the best clinical outcome in individual patient care. Thus, every health care provider is responsible for the management of his/her unique patient, based on the clinical presentation and management options available locally. REVIEW OF THE GUIDELINES This Guidelines was issued in 2021 and will be reviewed in 2026 or earlier if important new evidence becomes available. CPG SECRETARIAT Health Technology Assessment Unit Medical Development Division Level 4, Block EI, Parcel E Government Offices Complex 62590 Putrajaya, Malaysia Available on the following websites: http://www.malaysianheart.org http://www.moh.gov.my http://www.acadmed.org.my This is an update to the Clinical Practice Guidelines on UA/NSTEMI (published 2002 and 2011) It supersedes the previous CPGs on UA/NSTEMI (2002, 2011). 1 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 MESSAGE FROM THE DIRECTOR GENERAL OF HEALTH Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) accounted for 55.4% of all Acute Coronary Syndrome (ACS) reported from the National Cardiovascular Disease Database (NCVD) - ACS Registry between 2016 and 2017. NSTE-ACS including the non-ST elevation myocardial infarction and unstable angina is the dominant clinical manifestation of ACS in Malaysia hence ensuring the standardised and current clinical management for our clinicians is paramount for the safety of our patients. A multi-pronged approach has seen improvement in the management of ACS over the last decade, in line with the development of both treatments and healthcare service delivery. However, since the publication of the previous Clinical Practice Guidelines (CPG) for the management of NSTE-ACS in 2011, new diagnostic and therapeutic measures have been introduced and practised. Therefore, the publication of the refreshed version of the 2021 Third Edition Clinical Practice Guideline on the Management of ST-Elevation Myocardial Infarction is timely. Amongst the areas of focus in this brand-new CPG would be the in pre-hospital care, the use of cardiac troponins in the diagnostic work-up, a greater emphasis on risk stratification scores early in the inpatient management, and also the recommendation of an early invasive strategy for patients at the highest risk of adverse outcomes. I am delighted with the research contribution by the various clinical and academic groups for the reference in this CPG, and I encourage such endeavours to continue for the improvement in both care and outcomes in patients. This CPG complements others that focus on the risk factors associated with the condition, including its sister condition, ST-elevation ACS in the CPG STEMI, 2019. I thank the members of the Expert Panel and the External Reviewers, drawn from both the public and private sector of the Malaysian healthcare ecosystem, for their tireless work to produce this CPG. I would also like to acknowledge the National Heart Association of Malaysia and my colleagues at the Ministry of Health Malaysia for publishing this important update on the management of NSTE-ACS, 2021. Tan Sri Dato' Seri Dr. Noor Hisham Bin Abdullah Director-General of Health Malaysia 2 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 MEMBERS OF THE EXPERT PANEL Chairperson: Dr Jeyamalar Rajadurai Consultant Cardiologist Subang Jaya Medical Centre Members: (In Alphabetical Order) Dr Abdul Kahar Ghapar Consultant Cardiologist, Head of Cardiology, Hospital Serdang Dr Amin Ariff Nuruddin Consultant Cardiologist, Head of Cardiology, Institut Jantung Negara Dr Ahmad Tajuddin Mohamad Nor Consultant Emergency Physician, Hospital Tengku Ampuan Rahimah Dr Izwan Effendy Ismail Family Medicine Specialist, Klinik Kesihatan Puchong Dr Kauthaman A/L A Mahendran Consultant Physician and Head, Department of Medicine, Hospital Melaka Dr Lee Kun Yun Public Health Specialist, Institute for Health Management, Ministry of Health Dr Ong Mei Lin Consultant Cardiologist, Gleneagles Penang Dr Saari Mohamad Yatim Consultant Rehabilitation Physician, Hospital Serdang Dr Sabariah Faizah Jamaluddin Consultant Emergency Physician and Lecturer Department of Emergency Medicine, Faculty of Medicine, UiTM Dr Vengketeswara Rao Seetharaman Family Medicine Specialist, Klinik Kesihatan Kalumpang Dr Wardati Binti Mazlan Kepli Clinical Pharmacist, Hospital Serdang Dr Wan Azman Wan Ahmad Consultant Cardiologist, University Malaya Medical Centre 3 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 EXTERNAL REVIEWERS (In Alphabetical Order) Dr Adi Bin Osman Head of State, Emergency Physician, Hospital Raja Permaisuri Bainun Dr Ana Daliela Binti Masiman Consultant Pathologist, Hospital Melaka Dr Anwar Suhaimi Consultant Rehabilitation Physician, Cardiac Rehabilitation Services, University Malaya Medical Centre Dr Chan Hiang Chuan Consultant Emergency Physician, Hospital Umum Sarawak Dr Gan Chye Lee Consultant Physician, Hospital Melaka Dr Ismail Mohd Saiboon Professor and Emergency Physician Department of Emergency Medicine, UKM Medical Centre Dr Keshab Chandran Nair General Practitioner, Klinik Anis,17, Jalan Bunga Melur 2/18, Section 2, 40000 Shah Alam, Selangor Dr Khairi Bin Kassim @ Hashim Emergency Physician, Emergency & Trauma Department, Hospital Serdang Dr Leslie Charles Lai Chin Loy Consultant in Chemical Pathology and Metabolic Medicine, Gleneagles Kuala Lumpur Dr Lee Chuey Yan Consultant Cardiologist, Hospital Sultanah Aminah Dr Loi Siew Ling Head of Department, Emergency Physician, Hospital Bintulu 4 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 EXTERNAL REVIEWERS (In Alphabetical Order) Dr Mahathar Abd Wahab Emergency Physician, Emergency and Trauma Department, Hospital Kuala Lumpur Dr Mastura Hj Ismail Family Medicine Specialist, Klinik Kesihatan Seremban 2 Dr Mohd Anizan Bin Aziz Emergency Physician, Hospital Teluk Intan Dr Mohd Ghazali Ab Rashid Emergency Physician & Head of Department, Emergency Department, Hospital Raja Perempuan Zainab II Dr Mohd Lotfi Bin Hamzah Head of State, Emergency Physician, Hospital Sultanah Nur Zahirah Dr Mohamad Iqhbal Bin Kunji Mohamad Senior Lecturer and Emergency Physician, Department of Emergency Medicine, Universiti Teknologi MARA Dr Narul Aida Salleh Family Medicine Specialist, Klinik Kesihatan Kuala Lumpur Ms Nirmala Jagan Clinical Pharmacist, Hospital Kuala Lumpur Dr Noor Azleen Binti Ayop Head of State, Emergency Physician, Hospital Seberang Jaya Dr Ong Tiong Kiam Consultant Cardiologist, Sarawak Heart Centre Dr Rashidi Ahmad Emergency Physician, University Malaya Medical Centre Dr Ridzuan Bin Dato Mohd Isa Emergency Physician, Head of State, Hospital Ampang 5 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 EXTERNAL REVIEWERS (In Alphabetical Order) Dr Ruhaiza Mohamad Consultant Physician, Hospital Melaka Dr Sahimi Binti Mohamed Head of Clinical Section, Pharmacy Department, Hospital Tengku Ampuan Afzan Dr Saravanan Krishinan Consultant Cardiologist and Electrophysiologist, Hospital Sultanah Bahiyah Dr Shamsul Anuar Bin Asmee Emergency Physician and Head of Department Emergency and Trauma Department, Hospital Kulim Dr Siti Suhaila Hamzah Emergency Physician, Emergency & Trauma Department, Hospital Sungai Buloh Dr Sunita Bavanandan Consultant Nephrologist, Hospital Kuala Lumpur Dr Tan Maw Pin Consultant Geriatrician, University Malaya Medical Centre Dr Vengkata Prathap A/L Simanchalam Emergency Physician, Head of Department, Hospital Banting Dr V Paramananda Patient Advocate, Taiping Dr Zul Imran Bin Malek Abdol Hamid Emergency Physician, Emergency and Trauma Department, Hospital Pakar Sultanah Fatimah Muar 6 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 CONTENT PAGE STATEMENT OF INTENT 1 MESSAGE FROM THE DIRECTOR GENERAL OF HEALTH 2 MEMBERS OF THE EXPERT PANEL 3 EXTERNAL REVIEWERS 4-6 CONTENTS 7-8 RATIONALE AND PROCESS OF GUIDELINES DEVELOPMENT 9-15 GRADES OF RECOMMENDATION AND LEVELS OF EVIDENCE 16 LIST OF ABBREVIATIONS 17-20 WHAT’S NEW IN THE CURRENT GUIDELINES 21 SUMMARY 23-27 KEY MESSAGES 28-30 KEY RECOMMENDATIONS 31-34 FLOW CHARTS AND TABLES 35-42 1. INTRODUCTION 43-44 2. DEFINITION OF TERMS 44-47 3. PATHOGENESIS 47-48 4. DIAGNOSIS 48-55 4.1 History 4.2 Physical Examination 4.3 Electrocardiography 4.4 Cardiac Biomarkers 4.5 Other Diagnostic Modalities 5. RISK SCORES 55-62 5.1 Risk Scores to “Rule out ACS” 5.2 Risk scores for Prognostication in NSTE-ACS 5.3 Risk Scores for Bleeding 7 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 CONTENT PAGE 6. PRE HOSPITAL MANAGEMENT 62-66 6.1 For the General Public 6.2 Primary Care Clinics 6.3 Medical Emergency Coordination Centres (MECC) and Ambulance Responders 7. IN-HOSPITAL MANAGEMENT 66-79 7.1 Emergency Department 7.2. Levels of Care 7.3 Pharmacotherapy 7.4 Revascularization Strategies 8. NSTE-ACS IN SPECIAL GROUPS 80-85 8.1 NSTE-ACS in Older Persons 8.2 NSTE-ACS in Women 8.3 NSTE-ACS in Chronic Kidney Disease (CKD) 9. POST HOSPITAL DISCHARGE 85-89 9.1 Medications Post-Discharge 9.2 Follow-up Investigations 10. CARDIAC REHABILITATION 89-92 10.1 Cardiac Rehabilitation Programs (CRP) 10.2 Return to Physical Activity 10.3 Risk Factor Modification 10.4 Return to Sexual Activity and Fitness for Commercial Air Travel 11. MONITORING OF ACTIVITY AND QUALITY ASSURANCE 93 12. APPENDICES : I - XV 93-106 13. REFERENCES 111-131 14. ACKNOWLEDGEMENTS 131 DISCLOSURE STATEMENT 131 SOURCES OF FUNDING 131 8 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 RATIONALE AND PROCESS OF GUIDELINES DEVELOPMENT Rationale: Ischemic Heart disease is the main cause of mortality in Malaysia. Data from our National Cardiovascular Disease Database - Acute Coronary Syndrome (NCVD-ACS) Registry showed that the in-hospital, one month and 1-year mortality following NSTE-ACS is higher than that of other international registries. Thus, an update to our 2011 Clinical Practice Guidelines is timely. This CPG consists of statements that include recommendations intended to optimize patient care guided by a systematic review of evidence and assessment of the benefits and harms of alternative care options, reflecting the latest literature, expert consensus, and wherever possible, public stakeholder comment. This Guidelines has been prepared by a panel of committee members from the National Heart Association of Malaysia (NHAM) and Ministry of Health (MOH). The committee members were multidisciplinary and comprised cardiologists, internal, emergency and family medicine specialists and cardiac rehabilitation physicians from the government, private sector and universities. The external reviewers were also multidisciplinary and in addition to specialists, general practitioners were also included. Stakeholders - members of the general public - were also included as external reviewers. The committee made use of the following resources in developing this CPG :-  American College of Cardiology Foundation and American Heart Association (2010) Methodology manual and policies from the ACCF/AHA Task Force on Practice Guidelines  European Society of Cardiology (ESC) Governing Policies and Procedures for the Writing of ESC Clinical Practice Guidelines and  the Appraisal of Guidelines for Research and Evaluation [ AGREE II ] Tool Objectives: The objectives of this Guidelines are to provide guidance on:  Systematic evaluation of patients presenting with chest pain to the Emergency Department to reduce the number of “missed Myocardial Infarctions”.  Evidence-based therapeutic strategies in patients with NSTE-ACS to reduce the risk of recurrent Major Adverse Cardiac Events (MACE).  Strategies to optimize patient care and reduce potential harm among the different subsets of patients with NSTE-ACS within the existing local frame-work of healthcare. 9 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Process: A review was carried out of the medical literature on Myocardial Infarction (MI)/Non ST Elevation Acute Coronary Syndrome / Non ST Elevation MI (NSTEMI) / Unstable Angina (UA)/Acute Coronary Syndromes (ACS) published since the issuing of the last CPG in 2011. Literature search was carried out using the following electronic databases - PubMed and Cochrane Database of Systematic Reviews. The search was conducted for the period 2011 till 31st August 2019. The following MeSH terms or free text terms were used either singly or in combination: “Acute Coronary Syndrome”,”ACS”, “Myocardial infarction (MI)”; “NSTEMI”; Non ST Elevation Myocardial Infarction;” “UA”,” Unstable Angina”,”Non ST Elevation Acute Coronary syndrome”, “NSTE-ACS” “definition of MI”; “Myocardial injury”, “ECG criteria of NSTE-ACS”,”Rule out Protocols for ACS”; “Risk Scores for ACS”, “cardiac troponins”, “Pre-hospital Management of ACS”; “Oxygen therapy in ACS”; “Risk stratification scores in NSTE-ACS”; “Cardiac rehabilitation”, “secondary prevention post NSTE-ACS”, “management of NSTE-ACS in women, the elderly, persons with chronic renal disease.” The search was filtered to clinical trials and reviews, involving humans and published in the English language. The relevant articles were carefully selected from this huge list. In addition, the reference lists of all relevant articles retrieved were searched to identify further studies. Regional CPGs were also studied. Experts in the field were also contacted to obtain further information. International Guidelines mainly that from the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and the European Society of Cardiology (ESC) were used as references. The literature retrieved was appraised by members of the Expert Panel and all statements and recommendations made were collectively agreed by the group. The systemic reviews were conducted “in-house” and the committee appraised the quality of evidence collectively. The evidence was not systematically assessed for consistency, precision and directness. However, each of these attributes were implicitly judged when the committee appraised and graded the evidence and wrote the level of recommendation. The recommendations of the other international bodies – ACCF/ACC, ESC and The National Institute for Health and Care Excellence (NICE) Guidelines-were also studied to determine their applicability to the local population and heathcare. The grading of the evidence and the level of recommendation used in this CPG as outlined in page 16, were adopted from that used by the American College of 10 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Cardiology Foundation/ American Heart Association 2010 Methodology Manual and Policies by the ACCF/AHA Task Force on Practice Guidelines and the European Society of Cardiology Governing Policies and Procedures for Writing ESC Clinical Practice Guidelines 2017. After much discussion, the draft was then drawn up and submitted to the Technical Advisory Committee for Clinical Practice Guidelines, MOH Malaysia and key health personnel in the major hospitals of the MOH and the private sector and general public for review and feedback. Clinical Questions Addressed: There were several topics and subtopics that were formulated addressing the diagnosis and management of NSTE-ACS (UA+ NSTEMI) For diagnosis: In a person presenting with chest pain/ chest pain equivalent:  What features in the history would make one suspect this patient is having an ACS?  In a patient with suspected ACS, how do you differentiate NSTE-ACS and STEMI based on:  ECG  Cardiac biomarkers - cardiac troponins/ Creatine Kinase Myocardial Band (CKMB). How useful are these?  Is there a role for cardiac troponins to be available in primary healthcare (cost-effectiveness)?  Echocardiogram: is it a useful diagnostic tool?  Which patients presenting with chest pain in the ED can be safely sent home?  How do we risk stratify patients with NSTE-ACS?  Which patients require urgent referral for cardiac catheterization? For therapy, the topics and subtopics were formulated using the PICO method as follows: P: Population - Persons with NSTE-ACS and risk stratified using either the TIMI or GRACE scores (Appendix IV and V, page 96 and 97) and at:  Low risk of MACE  Intermediate risk of MACE  High risk of MACE  Very high risk of MACE 11 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 I: Intervention:  Oxygen vs no oxygen  Pharmacotherapy  Nitrates  Morphine  Antithrombotics: Antiplatelet therapy Anticoagulants  Heparin/ fondaparinux  Direct oral anticoagulants (DOAC)  Renin Angiotensin Blockers: Angiotensin converting enzyme inhibitors (ACE-I), Angiotensin receptor blockers (ARB)  β-blockers  Mineralocorticoid antagonists (MRA)  Statins  Interventional therapy - Percutaneous Coronary Intervention (PCI) C: Comparison:  Single antiplatelet therapy vs dual antiplatelet therapy (DAPT)  Ticlopidine vs clopidogrel vs prasugrel vs ticagrelor as second antiplatelet agent  DOAC + single antiplatelet vs DAPT  Low molecular weight heparin vs unfractionated heparin vs fondaparinux  ACE-I vs no ACE-I  Nitrates vs no nitrates  β-blockers vs no β-blockers  High dose statins vs no statins  Ivabradine vs no ivabradine  Trimetazidine vs no trimetazidine  PCI vs Medical therapy O: Outcome: 1. Reduction in major cardiovascular adverse events (MACE -MI, heart failure, stroke, cardiovascular disease (CVD) death) 2. Reduction in all-cause mortality 12 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Type of Question - Involves:  Therapy - Pharmacotherapy, PCI  Harm -  Increase in cardiovascular disease event rate (MACE -MI, heart failure, stroke, CVD death)  Increase in bleeding risk and stroke rate  Adverse effects due pharmacotherapy  Prognosis - Reduction in MACE-MI, heart failure, stroke, CVD death and improvement in all-cause mortality Type of Study  Systematic review and meta-analysis  Randomised controlled studies  Cohort studies  Registry data Thus, there were numerous clinical questions formulated. Examples of some of these Clinical Questions: 1. In a patient presenting with NSTE-ACS and with ongoing chest pains and at low risk of MACE (Major Cardiovascular Outcomes) is the administration of intravenous morphine for pain relief as compared to a non opiate, effective and safe? 2. In a patient presenting with NSTE-ACS and at low risk of MACE, taking into consideration the patient’s bleeding risks (as assessed by the PRECISE-DAPT score, Appendix VI page 98), are double antiplatelet agents more effective than a single antiplatelet agent, in reducing:  MI, heart failure, stroke, cardiovascular disease (CVD) death  All-cause mortality 3. Would an initial interventional therapy when compared to intensive medical therapy alone in a patient presenting with NSTE-ACS and at low risk of MACE result in a reduction in:  MI, heart failure, stroke, cardiovascular disease (CVD) death  All-cause mortality. 4. Would an initial interventional therapy when compared to intensive medical therapy alone in a patient presenting with NSTE-ACS and at very high risk of MACE result in a reduction in:  MI, heart failure, stroke, cardiovascular disease (CVD) death  All-cause mortality. 13 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Target Group: This Guidelines is directed at all healthcare providers including general practitioners, medical officers, general, family and emergency physicians and cardiologists. Target Population: All patients (older than 18 years) presenting with chest pain and who have been diagnosed to have NSTE-ACS based on the history, ECG and cardiac biomarkers. Period of Validity of the Guidelines: This guideline needs to be revised at least every 5 years or sooner if significant changes have occurred, or new data is available that would influence the recommendations made. Applicability of the Guidelines: This Guidelines was developed taking into account our local healthcare resources. The following are available at all specialist government hospitals.  ECG machines, measurement of cardiac biomarkers (including troponins), treadmill stress ECG’s and echocardiograms.  We have recommended that all specialist hospitals have facilities to measure cardiac troponins (preferably high sensitivity cardiac troponins). This should preferably be lab-based (depending on volume) or at least point of care (POC) kits. Cardiac troponins should replace the measurement of “cardiac enzymes”- lactate dehydrogenase, transaminases and creatine kinase.  Most of the medications that are recommended in this Guidelines are already present in the Malaysian standard drug formulary.  Very high risk/high risk patients should be identified early and transferred to hospitals with existing catheterization facilities. In accordance with the national health plan, the ministry has already proposed the setting up of catheterization laboratories in most of the state hospitals. This Guidelines aims to streamline management of cardiac patients and educate healthcare professional on strategies to optimize existing resources. We do not anticipate barriers to its implementation. 14 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Implementation of the Guidelines: The implementation of the recommendations of a CPG is part of good clinical governance. To ensure successful implementation of this CPG we suggest:  Increasing public awareness of CAD and its therapies.  Continuing medical education and training of healthcare providers.  Clinical audit - This is done by monitoring:  In - hospital mortality and morbidity in patients admitted with NSTE-ACS (NCVD-ACS registry)  Readmission rates for a cardiac related event in patients discharged with a diagnosis of NSTE-ACS. Elective admissions for cardiac procedures are excluded.  Documentation of the following; – In patients suspected of ACS, measurement and documentation of the Heart Score of the individual at ED. – Percentage of high-risk patients having their coronary angiogram performed < 48 hours when admitted to a PCI capable hospital. – In patients discharged with a diagnosis of NSTE-ACS, Medications at discharge:  Aspirin  P2Y12 inhibitor  high intensity statins Referral to a cardiac rehabilitation program Dr Jeyamalar Chairperson 15 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Table 1: Levels of evidence and grades of recommendation GRADES OF RECOMMENDATION I Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful and/or effective. II Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure/therapy. II-a : Weight of evidence/opinion is in favour of its usefulness/efficacy. II-b : Usefulness/efficacy is less well established by evidence/opinion. III Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful. LEVELS OF EVIDENCE A Data derived from multiple randomised clinical trials or meta-analyses. B Data derived from a single randomised clinical trial or large non-randomised studies. C Only consensus of opinions of experts, case studies or standard of care. Adapted from the  American College of Cardiology Foundation / American Heart Association and the European Society of Cardiology American College of Cardiology Foundation and American Heart Association (2010) Methodology manual and policies from the ACCF/AHA Task Force on Practice Guidelines. Available: http:// professional. heart.org/-/media/phd-files/guidelines-and-statements/methodology_manual_and_policies_ucm_319826.pdf.  European Society of Cardiology: Governing Policies and Procedures for the Writing of ESC Clinical Practice Guidelines. Available at https://www.escardio.org/static-file/Escardio/Guilines/About/Recommendation -Guidelines-Production.pdf. 16 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 LIST OF ABBREVIATIONS Abbreviation Description ABC Airway, Breathing, Circulation ABCD Airway, Breathing, Circulation and Defibrillation ACC American College of Cardiology ACE-I Angiotensin Converting Enzyme Inhibitor ACS Acute Coronary Syndrome ACT Activated Clotting Time ADP Adenosine diphosphate AF Atrial Fibrillation AHA American Heart Association AMI Acute Myocardial Infarction APTT Activated Partial Thromboplastin Time ARB Angiotensin Receptor Blocker AST Aspartate Aminotransferase AV Atrio-Ventricular BBB Bundle Branch Block Bd Bis Die (Twice Daily) BiPaP Bi-Level Positive Airway Pressure BMS Bare Metal Stents BP Blood Pressure CABG Coronary Artery Bypass Graft CAD Coronary Artery Disease CCU Cardiac Care Unit CHD Coronary Heart Disease CIN Contrast Induced Nephropathy CK Creatine Kinase CKD Chronic Kidney Disease CKD-EPI Chronic Kidney Disease Epidemiology Collaboration CK-MB Creatine Kinase-Myocardial Band CPG Clinical Practice Guidelines 17 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Abbreviation Description CPR Cardiopulmonary Resuscitation CrCL Creatinine Clearance CRP Cardiac Rehabilitation Programme cTn Cardiac Troponins cTnI Cardiac Troponin I cTnT Cardiac Troponin T CoV Coefficient of Variation CVD Cardiovascular Disease CPAP Continuous Positive Airway Pressure D5W 5% Dextrose in Water DAPT Dual Antiplatelet Therapy DBT Door to Balloon Time DES Drug Eluting Stents DM Diabetes Mellitus DNT Door to Needle Time DOAC Direct Oral Anticoagulants DVT Deep Venous Thrombosis ECG Electrocardiogram EF Ejection Fraction eGFR Estimated Glomerular Filtration Rate ESC European Society of Cardiology FMC First Medical Contact GFR Glomerular Filtration Rate Gp Glycoprotein GRACE Global Registry of Acute Coronary Events GTN Glyceryl Trinitrate HF Heart Failure HRT Hormone Replacement Therapy Hs-cTn High-Sensitivity Cardiac Troponins 18 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Abbreviation Description HTA Health Technology Assessment IABP Intra-Aortic Balloon Pump IC Intracoronary ICD Implantable Cardioverter-Defibrillator INR International Normalised Ratio IO Intraosseous IRA Infarct-Related Artery IV Intravenous LBBB Left Bundle Branch Block LDH Lactate Dehydrogenase LDL Low Density Lipoprotein LDL-C Low Density Lipoprotein Cholesterol LMWH Low Molecular Weight Heparin LV Left Ventricular LVEF Left Ventricular Ejection Fraction LVH Left Ventricular Hypertrophy MACE Major Adverse Cardiovascular Events MDRD Modification of Diet in Renal Disease MI Myocardial Infarction MOH Ministry of Health Malaysia MRI Magnetic Resonance Imaging MSCT Multi-Slice Computed Tomography NaCl Sodium Chloride NaHCO3 Sodium Bicarbonate NCVD National Cardiovascular Disease Database NHAM National Heart Association Malaysia NSAID Non-steroidal Anti-Inflammatory Drug NSTEMI Non ST Segment Elevation Myocardial Infarction OAC Oral Anticoagulants 19 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Abbreviation Description Od Once daily PCI Percutaneous Coronary Interventions PCWP Pulmonary Capillary Wedge Pressure PEA Pulseless Electrical Activity PHC Pre Hospital Care RBBB Right Bundle Branch Block ROSC Return of Spontaneous Circulation r-TPA Recombinant Tissue Plasminogen Activator RV Right Ventricular RVI Right Ventricular Infarction SBP Systolic Blood Pressure SC Subcutaneous Scr Serum Creatinine SpO2 Pulse Oximeter Oxygen Saturation STEMI ST Segment Elevation Myocardial Infarction Tds Ter Die Sumendus (Three Times Per Day) TIA Transient Ischaemic Attack TIMI Thrombolysis in Myocardial Infarction TMP TIMI Myocardial Perfusion Grade TNK-tPA Tenecteplase TVR Target Vessel Revascularization UFH Unfractionated Heparin ULRR Upper Limit Reference Range URL Upper Reference Limits VF Ventricular Fibrillation VPC Ventricular Premature Contractions VSD Ventricular Septal Defect VT Ventricular Tachycardia 20 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 WHAT’S NEW IN THE CURRENT GUIDELINES Previous CPG Current CPG NSTE-ACS 2021 UA/NSTEMI 2011 Use of the term Referred to as NSTE-ACS is a combination of NSTE-ACS unstable angina (UA)  Unstable Angina (UA) and and Non ST Elevation  Non ST Elevation MI (NSTEMI) Myocardial Infarction (NSTEMI) Definition of In accordance with the 4th Universal Infarction (MI) Definition (Section 2, pages 44 - 47) Myocardial Distinguishing No clear differentiation Myocardial injury is reflected by a level the difference between myocardial above the 99th percentile upper reference between injury and MI limit (URL) of troponin. Myocardial injury myocardial injury may be due to: and Myocardial  Ischemia Infarction (MI)  Non-ischemic causes - Recognition MI is myocardial injury due to ischemia. that all myocardial NSTE- ACS is MI without ST elevation injury is not seen on the resting ECG. necessarily due to MI Pre-hospital Brief statement about  Providing a structured format of Care/personnel Pre-hospital response to an emergency call for Care/personnel “chest pain.”  Ambulance responders should be trained and equipped to perform an ECG (with the use of Advanced Cardiac Care Device which is capable of ECG recording,transmission, and real-time ECG monitoring and telemetry).  If the ECG shows STEMI or the patient with NSTE-ACS has ongoing/ recurrent chest pain, they should be considered for immediate transfer to a PCI-capable hospital. High-risk unstable patients should be taken to the nearest hospital for stabilization first. 21 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Previous CPG Current CPG NSTE-ACS 2020 UA/NSTEMI 2011 Use of cardiac No mention of hs-cTn  Recommendation for using cTn, troponins (cTn), preferably hs-cTn as the cardiac preferably High biomarker of choice in patients Sensitivity cardiac suspected to be having an ACS. troponins hs-cTn  Guide on how to interpret elevated cardiac troponin levels. (Table 2, page 38 & Appendix II, page 94)  MI is defined as a rise and fall in cTn levels and with either clinical history of ischemic pain, ECG or \ echocardiographic features consistent with MI or in the presence of an intracoronary thrombus. Risk Scores No mention of “rule  In patients suspected of having an ACS, out ACS” processes in use of “rule-out ACS” Flowchart 1, page patients suspected of 35 in the ED in combination with the having ACS. HEART score (or modified HEART score.)  In patients with definite NSTE-ACS, importance of risk stratification using either clinical features, (Table 3, page 39) TIMI or GRACE scores. (Appendix IV & V, pages 96 & 97 )  In patients with definite NSTE-ACS, advocating the use of the PRECISE-DAPT score to assess bleeding risk. (Appendix VI, page 98) Invasive strategy-  Patients with  Patients with definite NSTE-ACS who Timing of refractoryangina and/ after risk stratification are at: intervention or hemodynamic  Very high-risk should undergo an instability should be immediate invasive strategy ( 2 hours after hs-cTn (done < 2 hours after onset of symptoms) onset of symptoms) Repeat 2nd cTn - 3 hours later. If hs-cTn - 2 hours later < 99th percentile and > 99th percentile or < 50% change in levels > 50% change in levels within a 3-hour period*** within a 3-hour period*** Pain free and Still having pain and/or HEART score < 3** or HEART score > 3** or TIMI score 0 or 1** TIMI score ≥ 2** Other diagnosis excluded Discharge from ED+ for early outpatient cardiology Admit (in the absence of cardiology-internal medicine) consult # 0/3 refers to time from first blood test *Correlate the result with the clinical condition of the patient (Table 2, page 38) **If cTn use HEART score for scoring and for hs-cTn use modified HEART score or TIMI score ***If initial baseline cTn (or hs-cTn) is markedly > 99th percentile, a change of >20% is significant. If the baseline is < or around the 99th percentile URL, a change of at least 50% is required to be significant. + Discharge Care Plan after “Rule out ACS” Keep scheduled appointment for further cardiac assessment. Should chest pain/discomfort recur before your appointment, please go the nearest hospital. 35 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 FLOWCHART 2: Non-invasive investigation of Low Risk Patients with NSTE-ACS* LOW RISK PATIENTS WITH NSTE-ACS# Normal ECG, Abnormal ECG, Good Exercise Tolerance Limited Exercise Tolerance Exercise Stress Test Equivocal * Exercise / Dobutamine Stress Echocardiogram or * Cardiac MRI or * CT coronary angiogram Negative Test Positive Equivocal / Positive Test Risk Factor Reduction + Invasive Coronary Medical Therapy for CAD Angiogram * The choice of investigation will depend on the available resources and expertise. # Low risk patients have: no angina in the past no ongoing angina no prior use of antianginal therapy normal ECG normal cardiac biomarkers younger age group normal LV function Patients who have undergone revascularization and with residual/recurrent ischemia or a change in symptoms should be investigated as above. All Intermediate/High Risk NSTE-ACS patients should be considered for coronary angiography and revascularization. 36 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 FLOW CHART 3: Pathogenesis of ACS Presentation Ischemic Chest Discomfort Provisional Diagnosis ACS ECG No ST Elevation ST Elevation Normal Elevated Elevated Cardiac Biomarkers Final Diagnosis Unstable NSTEMI STEMI Angina MI NSTE-ACS ACS Adapted from Amsterdam EA, Wenger N, Brindis RG et al. “2014 ACC/AHA Guidelines for the management of patients with Non ST Elevation Acute Coronary Syndromes” Circulation. 2014;130:e344-e426. 37 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Table 2: Interpreting Cardiac Troponins Elevated Cardiac Troponins (> 99th percentile) Troponin Levels Rise and/or Fall* Troponin Levels Stable# With Acute Ischemia** Without Acute Ischemia** Acute Myocardial Acute Myocardial Chronic Myocardial Infarction*** Injury (Not MI) Injury ACS Non-ACS Cardiac Eg: STEMI NTE-ACS Coronary Heart Failure Chronic structural Increased Inflammation- heart disease demand Myocarditis Chronic kidney (stable CAD) Pericarditis disease Spasm Infection - Embolism Viral myocarditis Hypertension Stress Analytical errors (small vessel) cardiomyopathy Assay based PCI/Cardiac Sample based surgery Non cardiac (hemolysed specimen) Sepsis Non coronary Renal failure Global hypoxia Toxicity hypoperfusion - anthracyclines Stroke * A repeat cTn may be necessary depending on the clinical condition of the patient and the physician’s judgement. ** Ischemic thresholds vary substantially in relation to the magnitude of the stressor and the extent of underlying cardiac disease. *** Requires a rise and/or fall of troponins above the 99th percentile URL together with evidence of ischemia with at least one of the following: 1) Ischemic type chest pain of >30 mins or, 2) electrocardiography (ECG) changes of new ischemia or, 3) development of pathologic Q-waves in the ECG or 4) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. # Stable denotes ≤20% variation of troponin values in the appropriate clinical context. Adapted from: Thygesen K et al. Fourth universal definition of myocardial infarction. Eur Heart J 2019; 40 (3): 237-269 Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2012; 60(23):2427-2463 38 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Table 3: Risk stratification for NSTE-ACS Very-High-Risk Criteria  Haemodynamic instability or cardiogenic shock  Recurrent or ongoing chest pain refractory to medical treatment  Recurrent dynamic ST-T wave changes +/- intermittent ST-elevation  Life-threatening arrhythmias or cardiac arrest  Acute heart failure  Mechanical complications of MI High-Risk Criteria  Rise or fall in cardiac troponin compatible with MI  Dynamic ST- or T-wave changes (symptomatic or silent)  GRACE score >140  TIMI risk score >4 Intermediate-Risk Criteria  Diabetes mellitus  LVEF 109 and 1 year) in all patients post NSTE-ACS with no angina / ischemia and normal LV function. + ACE-Is I A Started on first day and continued long-term (>1 year) for patients with LVEF ≤40%, anterior infarcts and diabetes. IIb B Routine administration in all patients post NSTE-ACS > 1 year. ARBs I B Started on first day and continued long-term (>1 year) for patients with LVEF ≤40%, anterior infarcts and diabetes. IIb B Routine administration in all patients post NSTE-ACS > 1 year. Nitrates, CCB, IIa B Indicated for residual/recurrent Ivabradine, ischemia. ranolazine, trimetazidime 40 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Table 6: Clinical Classification of MI Type 1: Spontaneous MI due to coronary athero-thrombosis Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. Type 2: MI secondary to an imbalance between myocardial oxygen demand and supply unrelated to acute coronary athero-thrombosis MI that occurs due to an imbalance between myocardial oxygen supply and/or demand. It may occur in the presence of coronary atherosclerosis without plaque rupture or in the absence of atherosclerosis e.g., coronary endothelial dysfunction, coronary artery spasm, coronary embolism, coronary artery dissection, tachy/bradyarrhythmias, anemia, respiratory failure, sepsis, hypotension, and hypertension with or without left ventricular hypertrophy (LVH). Type 3: MI resulting in death when biomarker values are unavailable Cardiac death with symptoms suggestive of myocardial ischemic and presumed new ischemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected. Type 4a: MI related to PCI MI associated with PCI is arbitrarily defined by elevation of cardiac troponin (cTn) values 5 x > 99th percentile URL in patients with normal baseline values (≤ 99th percentile URL) or a rise of cTn values > 20% if the baseline values are elevated but are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow-or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality is required. Type 4b: MI related to stent thrombosis MI associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarkers values with at least one value above the 99th percentile URL. Type 5: MI related to coronary artery bypass surgery (CABG) MI associated with CABG is arbitrarily defined by elevation of cardiac biomarker values 10 x 99th percentile URL in patients with normal baseline cTn values (99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Adapted from Thygesen K et al. Fourth universal definition of myocardial infarction. Eur Heart J 2019; 40 (3): 237-269 41 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Table 7: Performance and Outcome Measures PERFORMANCE MEASURES DOCUMENTATION OF THE FOLLOWING TARGETS Access to hs Troponin Testing in all EDs = 50% Total number of EDs using hs-cTn x 100% Total number of EDs Measurement and Documentation of HEART Score at 70% Emergency Department = Total number of patients with suspected ACS for which HEART score is documented x 100% Total Number of patients with suspected ACS seen in ED Percentage of High-Risk Patients Admitted to PCI Capable 50% Hospitals and Undergoing Angiogram Within 48 hours = Total number of high-risk patients undergoing coronary angiogram within 48 hours x 100% Total Number of high-risk patients admitted Medications at Discharge:  Aspirin 90%  P2 Y12 inhibitors 90%  High intensity statins 90% Total number of patients with NSTE-ACS who were discharged with aspirin (or P2 Y12 inhibitors ) or (high intensity statins) x 100% Total Number of patients with NSTE-ACS who were discharged Cardiac Rehabilitation = 50% Total number of patients with NSTE-ACS who were referred for cardiac rehabilitation x 100% Total Number of patients with NSTE-ACS who were discharged OUTCOME MEASURES In-hospital mortality and morbidity in patients admitted with ACS (NCVD registry). Readmission rates for a cardiac related event in patients discharged with a diagnosis of ACS. Elective admissions for cardiac procedure are excluded. 42 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 1. INTRODUCTION Ischemic heart disease (IHD) remains the principal cause of death in Malaysia. In 2017, IHD was responsible for 13.9% of deaths, followed by pneumonia (12.7%) and cerebrovascular diseases (7.1%). It is the principal cause of death for all major ethnic groups being highest among Indians (19.5%),13.3% Bumiputera (12.3% Malays, others 1.01%), and 13.2% Chinese.1 Patients with IHD may present with stable coronary artery disease (CAD) - (now called - Chronic Coronary Syndromes) or acute coronary syndrome (ACS). ACS is a clinical spectrum from NSTE-ACS (combination of unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI)) to ST elevation myocardial infarction (STEMI). From the Malaysian National Cardiovascular Disease Database Acute Coronary Syndrome (NCVD-ACS) Registry 2016-2017: 2  44.6% of ACS patients were STEMI.  55.4% of ACS patients were NSTE-ACS (28.0% were NSTEMI and 27.4% were UA). Patients with NSTE-ACS were older (60.5 vs 56.3 years), more likely females (27.2% vs 14.2%) and had more CVD risk factors (comorbidities) compared to those who presented with STEMI. 2 Of those presenting with NSTE-ACS:2  42.2% were in the intermediate-high TIMI risk score  35.1% were in the intermediate risk group - (TIMI 3 & 4)  7.1% were in the high-risk group - (TIMI 5,6 & 7)  The in-hospital mortality was 7.5%. Compared to the previous registry data, our patients are now receiving more Guideline Directed Therapy (GDT). The use of DAPT and statins were more than 90%.2 More patients underwent coronary angiography during the index admission and 35.9% of NSTEMI and 20.2% of patients with UA had percutaneous coronary intervention (PCI).2 The in-hospital, 30-day and 1-year mortality were:2  7.5%, 11.5% and 23.6% for NSTEMI respectively  1.0%, 2.2% and 9.6% for UA respectively. These figures are slightly lower than that seen in the NCVD 2014-2015 but still higher than that of other registries.3-6 (Table 4, page 39) 43 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 The Malaysian Clinical Practice Guidelines (CPGs) on Stable Coronary Artery Disease 2018, 2nd Ed and ST Elevation Myocardial Infarction 4th Ed, 2019 were recently updated.7,8 The last CPG on UA/NSTEMI was published in 2011. Since then, there have been significant advances in the understanding of the pathophysiology and management. Thus, an update is timely to keep abreast with contemporary evidence. Key Messages 1#:  IHD remains the principal cause of death in Malaysia.  Our NCVD-ACS registry shows that our in-hospital, 30-day and 1-year mortality is still high despite being lower than in previous years. Our figures are higher than those in other international registries. (Table 4, page 39) 2. DEFINITION OF TERMS ACS is a clinical spectrum of IHD that develops because of an imbalance between myocardial oxygen demand and supply. It is usually due to a reduction in supply. Depending upon the acuteness of onset and the degree of coronary occlusion, it can range from: (Flowchart 3, page 37)  Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS). This is a combination of:  Unstable angina (UA) and  Non-ST elevation myocardial infarction (NSTEMI)  ST elevation myocardial infarction (STEMI) The pathology is dynamic. A patient presenting with UA may progress to NSTEMI or even STEMI. 2.1 Unstable Angina Patients with UA are a heterogenous group. According to Braunwald’s classification, updated in 2000, UA may be classified as (Appendix I, page 93)9 : I. New onset of severe angina or accelerated angina; no rest pain II. Angina at rest, subacute - Angina at rest within past month but not within preceding 48 hours. III. Angina at rest, acute - Angina at rest within 48 hours It may be further classified according to clinical circumstances into either : A) Secondary - develops in the presence of extracardiac disease B) Primary - develops in the absence of extracardiac disease C) Post-infarct - develops within 2 weeks of an acute MI In UA, myocardial injury is absent and cardiac biomarkers (troponins-cTn) are normal. In myocardial injury, cardiac biomarkers are raised. 44 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 2.2 Myocardial Infarction 2.2.1 Definition of Myocardial Injury and Myocardial Infarction It is important to distinguish between myocardial injury and Myocardial Infarction (MI). Myocardial injury may be due to:10  Ischemia - MI and/or  Non-ischaemic causes (eg. myocarditis, renal failure) MI is myocardial injury due to ischemia and is defined pathologically as myocardial cell death due to prolonged ischemia.10 2.2.1.1 Cardiac Biomarkers in the Diagnosis of Myocardial Injury and Myocardial Infarction The cardiac biomarkers of choice for the diagnosis are the cardiac troponins - cTn (both I and T), preferably high-sensitivity (hs-cTn). Elevation of cTn indicates myocardial necrosis. A level above the 99th percentile Upper Reference Limit (URL) is abnormal and indicative of myocardial injury.10 All locally available commercial laboratory-based assays indicate this level, the exact value varying depending on the reagents and assays used. The point of care (POC) kits, however, although giving a more rapid result, are not sensitive enough to detect this low level. With the current definition, UA patients in Braunwald’s Classification Stage III b, will be re-classified as NSTEMI. In one study, this re-classification increased the diagnosis of MI by 47%.11 This re-classification is of prognostic importance because these patients will now be treated more aggressively with GDT.12 cTn should always be interpreted in the clinical setting. Many cTn elevations, especially below certain cut-off points and cTn elevations without a rise and fall, are myocardial injuries and not MI (Table 2, page 38 & Appendix II, page 94). A rise and/or fall in the cTn level is indicative of acute injury, while a persistently elevated level is indicative of chronic injury10 (Table 2, page 38). Persistently elevated cTn levels such as that present in those with pre-existing CAD, impaired renal function, and persons older than 75 years appear predictive of a higher long-term mortality.13 According to the 4th Universal definition, MI is diagnosed when there is a significant rise and/or fall in cTn, with at least one value above the 99th percentile URL, and accompanied with at least one of the following:10  Clinical history consistent with chest pain of ischemic origin of > 30 minutes.  ECG changes of ischemia/infarction and/or the development of pathological Q waves.  Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. 45 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021  Identification of an intracoronary (IC) thrombus by angiography or autopsy. The exact value for the rise and fall is not addressed in most guidelines. The criteria for determining a pathological rise between two serial cTn values are assay-dependent.10 The National Academy of Clinical Biochemistry Guidelines and an expert consensus committee have suggested that in patients with possible ACS and baseline (initial result) cTn (or hs-cTn) results:10,14-16  Markedly above > 99th percentile URL, changes in concentrations of >20% from baseline should be used to define an MI.  < 99th percentile URL and especially with hs-cTn assays, a change of 50-60% from baseline has been suggested to overcome biological and analytical variations. The assays used should have a coefficient of variation (CoV) of < 10% at the 99th percentile URL.10,14-16 (Section 4.4, pages 51-54). 2.2.1.2 ECG in the Diagnosis of Myocardial Injury and Myocardial Infarction In myocardial injury, the ECG is either normal or showing non-specific changes and without the typical features of ischemia/infarction. MI may be STEMI or NSTE-ACS based on the ECG. (Flowchart 3, page 37) STEMI is diagnosed when there is:  ST elevation of ≥ 1 mm in 2 contiguous leads including right precordial leads# or  A new onset LBBB in the resting ECG  In a patient with ischemic type chest pains of > 30 minutes and  Accompanied by a rise and fall in cardiac biomarkers. # In leads V2-V3 the cut-off point is ≥ 0.25 mV in males < 40 years, ≥ 0.2 mV in males ≥ 40 years and ≥ 0.15 mV in females and in posterior chest leads V7-9 ≥ 0.05 mV and ≥ 0.1 mV in men < 40 years.10 In NSTE-ACS, ST elevation is absent on the resting ECG. UA and NSTEMI differ from each other:  In NSTEMI, the ischemia is severe enough to cause sufficient myocardial injury to release detectable cardiac biomarkers. The diagnosis of NSTEMI is established if a cardiac biomarker is detected. Often, there is a lapse of time from myocardial injury before these biomarkers can be detected. As such, in the early stages, UA and NSTEMI often cannot be differentiated.  In NSTEMI, ST/T changes may be present in the ECG, whereas in UA they are usually absent and even if they are present, are usually transient. 46 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 Key Messages 2#:  Acute Coronary Syndrome is a clinical spectrum of IHD that develops because of an imbalance between myocardial oxygen demand and supply.  Depending upon the acuteness of onset and the degree of coronary occlusion, it can range from (Flowchart 3, page 37):  Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS). This is a combination of: Unstable angina (UA) and Non-ST elevation myocardial infarction (NSTEMI)  ST elevation myocardial infarction (STEMI)  In UA, myocardial injury is absent and cardiac biomarkers (cTn) are normal.  Myocardial injury can lead to cell death and cardiac biomarkers are raised. It may result from severe ischemia and/or non ischemic causes (e.g., myocarditis).  Myocardial Infarction (MI) is myocardial injury due to ischemia. Key Messages 3#:  According to the 4th Universal definition, MI is diagnosed when there is a significant rise and/or fall in cTn, with at least one value above the 99th percentile URL, and accompanied with at least one of the following:2  Clinical history consistent with chest pain of ischemic origin of > 30 minutes.  ECG changes of ischemia/infarction and/or the development of pathological Q waves.  Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.  Identification of an intracoronary (IC) thrombus by angiography or autopsy.  MI may be STEMI or NSTE-ACS based on the ECG. 3. PATHOGENESIS ACS is commonly due to atherosclerotic plaque rupture, fissure or ulceration with superimposed thrombosis and coronary vasospasm. Depending on the acuteness of onset and the degree of occlusion and the presence of collaterals, patients can present as NSTE-ACS or STEMI. In NSTE-ACS the thrombus is either non-occlusive or there is complete thrombosis of a vessel that is well collateralized. The majority (66%-78%) of ACS arise from lesions with 70% stenosis.17-20 From postmortem studies and in vivo studies using intravascular ultrasound, four pathologic pathways to ACS have been postulated:21 MI can be classified as 5 types depending on the pathology, clinical features, prognosis and treatment strategies.10 (Table 6, page 41). This CPG focuses on NSTE-ACS which is usually either: 47 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021  Type 1 MI (spontaneous MI related to atherosclerotic plaque rupture, with ulceration, fissuring, erosion or dissection) or  Type 2 MI (often due to an imbalance between myocardial oxygen supply and/or demand. It may occur in the presence of coronary atherosclerosis without plaque rupture or in the absence of atherosclerosis). Type 2 MI is an important cause of ACS in the elderly. Distinguishing Type 2 MI from troponin release due to non-coronary diseases is often difficult and challenging (Table 2, page 38 & Appendix II, page 94) Key Messages 4#:  MI can be classified as 5 types depending on the pathology, clinical features, prognosis and treatment strategies. (Table 6, page 41). This CPG focuses on NSTE-ACS which is usually either:  Type 1 MI (spontaneous MI related to atherosclerotic plaque rupture, with ulceration, fissuring, erosion or dissection) or  Type 2 MI (often due to an imbalance between myocardial oxygen supply and/or demand. It may occur in the presence of coronary athero sclerosis without plaque rupture or in the absence of atherosclerosis). This is an important cause of ACS in the older person.  The majority (66%-78%) of ACS arise from lesions with 70% stenosis. 4. DIAGNOSIS 4.1 History The symptoms of NSTE-ACS may be indistinguishable from that of STEMI. These include:  Chest pain  This is the presenting symptom in most patients. Typical anginal chest pain has traditionally been described as a central pain or pressure, aggravated by emotional or physical stress and relieved by rest or GTN.  Features that increase the probability of ischemic chest pain are pain radiating to both arms, pain similar to prior ischemic episodes, a change in the pattern of pain over the past 24 hours and associations with sweating22,23 and exertion.  Features that reduced the probability that the chest pain is ischemic in origin is variation with respiration or position, localisation to a point, pain reproduced on palpation and described as sharp or stabbing.22-26  The relief of symptoms after nitrate administration is not specific for angina pain neither is relief with the “GI cocktail” indicative that it is non-cardiac.27,28 48 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021  Chest pain at rest carries a worse prognosis than symptoms elicited during physical exertion. In patients with intermittent symptoms, an increasing number of episodes preceding the index event also adversely affects prognosis.29  Other symptoms  8% of ACS patients did not present with chest pain.30 They were more likely to be women, diabetics and the elderly.  Atypical symptoms or angina equivalents included dyspnea (50%), unexplained sweating (25%), nausea and vomiting (24%), syncope and presyncope (19%), fatigue and epigastric discomfort.30  Shoulder pain, sweating and a higher symptom distress score were more likely to indicate an ischemic origin of the symptoms.22-24 In patients with these presentation(s) and with a prior history of coronary artery disease (CAD) including prior abnormal stress test and peripheral arterial disease, diabetes and other CVD risk factors and renal disease and a family history of premature CVD, the index of suspicion of ACS should be high.22,31-33 Traditional cardiac risk factors although not helpful for the confirmation or exclusion of ACS, help raise the suspicion that symptoms may be ischemic in origin.34 There are cross-cultural and gender differences in symptoms reported by patients with suspected ACS.35,36 Such differences are however not clinically relevant because most of the symptoms display limited diagnostic value for ACS.35 "Atypical" symptoms cannot rule out ACS, while "typical" symptoms cannot rule it in. Therefore, if a patient has symptoms that are compatible with ACS and an alternative cause cannot be identified, clinicians must strongly consider the need for further investigations.37 The diagnosis of ACS is more frequently missed in:38,39  women  those presenting with dyspnea  in the presence of a normal ECG and  in the presence of comorbidities These patients had higher mortality than those who have received appropriate GDT following a diagnosis of ACS.30,37-39 4.2 Physical Examination The physical examination in ACS is generally unremarkable. The objective of the physical examination is to identify:  Possible etiologies such as aortic stenosis, hypertrophic cardiomyopathy, signs of hypercholesterolemia (xanthomas, xanthalesmas). 49 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021  Precipitating causes such as uncontrolled hypertension, anemia, thyrotoxicosis, infection.  Consequences of NSTE-ACS such as hypotension, heart failure and arrhythmias.  Other comorbid conditions such as lung disease, peripheral vascular disease. Presence of left ventricular failure (hypotension, respiratory crackles or S3 gallop) and arrhythmias carry a poor prognosis. Carotid bruits or peripheral vascular disease indicates extensive atherosclerosis and a higher likelihood of concomitant CAD. In addition, the physical examination may help identify other causes for the chest pain e.g., pericardial rub indicating pericarditis, tracheal shift and unequal air entry indicating pneumothorax, low oxygen saturation and unilateral swollen tender calf muscles suggesting pulmonary embolism, and vesicles and scabs for herpes zoster. 4.3 Electrocardiography (ECG) The ECG adds support to the diagnosis and provides prognostic information.40-45 A recording made during an episode of chest pain is particularly valuable. Wherever possible, an ECG should be performed at the First Medical Contact I,C (FMC) as this increases the likelihood of recognising transient changes.46 It should be performed within 10 minutes of FMC.47 In a small prospective study, 12.5% of pre-hospital ECGs in patients who were alert and experiencing chest pain or other symptoms consistent with those caused by myocardial ischemia had clinically significant abnormalities that were transient and not seen on the initial ECG done in the Emergency Department. 46 I,C All ambulances, government and private clinics should be equipped with 12-lead ECG-capable devices. I,C These should have computer-generated interpretations and wherever possible, this should be reviewed by trained personnel. These computer- generated ECG reports have a wide variation in the proportion false-positive (0% to 42%) and false-negative (22% to 42%) results. Thus, it should not be used as the sole means to diagnose ACS.48,49 50 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 ECG features that were associated with the highest 30-day incidence of death or reinfarction in ACS patients were44:  A combination of ST elevation (of at least 0.5 mm in at least 2 contiguous leads) and ST depression (of at least 0.5 mm in 2 contiguous leads) - (12.4%)  ST-segment depression of greater than 0.5 mm (alone or with concomitant T-wave inversion - (10.5%)  ST-segment elevation of at least 0.5 mm in at least 2 contiguous leads - (9.4%)  Isolated T wave inversion (>1 mm in leads including the normalisation of a known negative T-wave) - (5.5%). Other possible ECG changes include flat T waves, T inversions in a non-dominant R wave lead, presence of Q waves and poor R wave progression in the anterior chest leads. A new (or presumed new onset) LBBB and should be treated as STEMI. I,C A normal ECG does not exclude NSTE-ACS.49 Serial ECGs should be performed as the changes may evolve. I,C We recommend all patients be provided a copy of their ECG for personal keeping for comparison at future health encounters. A missed diagnosis of ACS carries a worse prognosis.38,39 4.4. Cardiac Biomarkers Cardiac troponins (cTn) T and I are the most sensitive and specific biomark- I,A ers for myocardial injury and necrosis.10,50 Where there is access to cTn testing, other biomarkers (AST, LDH, CK, CKMB and myoglobin) are not useful for the initial diagnosis of acute MI.51 This is due to their lower sensitivity and specificity.52,53 CKMB may be used to monitor for reinfarction. IIb, B In settings where10,54 cTns are not available, CKMB will be the alternate but less preferred option. After acute MI, cTn becomes detectable at 6 hours using the conventional older cTn assays and may remain elevated for up to 14 days. Hs-cTn assays detect cTn release at an earlier time point than the older cTn tests leading to an improved early sensitivity for a diagnosis of MI.15 cTn are markers of myocardial necrosis and not specific markers for MI. The 51 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF NON-ST ELEVATION MYOCARDIAL INFARCTION (NSTE-ACS) 3RD EDITION 2021 rise and/or fall of cTn with at least one value greater than the 99th percentile is