MOH/P/PAK/206.10|GU) CLINICAL PRACTICE GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS July 2010STATEMENT OF INTENT This clinical practice guidelines (CPG) is meant to be a guide for clinical practice, based on the best available evidence at the time of development. Adherence to these guidelines may not necessarily guarantee the best outcome in every case. Every health care provider is responsible for the management of his/her patient based on the clinical picture presented by the patient and the management options available locally. PERIOD OF VALIDITY This CPG was issued in 2012 and will be reviewed in 5 years or sooner if new evidence becomes available. CPG SECRETARIAT c/o Health Technology Assessment Unit Medical Development Division Ministry of Health Malaysia 4th Floor, Block E1, Parcel E 62590, Putrajaya. Electronic version available on the following website: http://www.moh.gov.my http://www.acadmed.org.my http://www.malaysianheart.orgMESSAGE FROM DIRECTOR GENERAL OF HEALTH, MALAYSIA Malaysia is now being confronted with the rising epidemic of cardiovascular risk factors. Data from the Third National Health and Morbidity Survey (NHMS ll) in 2006 showed that 63% of Malaysians had at least one cardiovascular risk factor, 33% had two risk factors and 14% had three or more risk factors. Hypertension remains the number one risk factor with a prevalence rate of 38%, followed by central obesity (37%), hypercholestrolaemia (24%) and hyperglycaemia (15%). The cardiovascular risk-factor clustering provides a clear impression of the true cardiovascular disease burden in the population. Coronary artery disease is one of the most rampant NCD in the world. It is the major cause of morbidity and mortality in our hospitals. Data from MOH hospitals in 2010 has shown that diseases of the circulatory systems (which also include cerebrovascular diseases) accounted for 25.4% of total deaths. This makes cardiovascular diseases as the main cause of death in MOH hospitals. Currently there are much pharmacological and technological advancement in the management of cardiovascular diseases. However | firmly believe that the appropriate management of patients with heart diseases is beyond prescribing the latest drugs or stents. These are important and necessary of course, nevertheless, we must not lose sight of the central role of therapeutic lifestyle changes such as a healthy balanced diet, regular aerobic exercise and reduction and cessation of unhealthy habits such as tobacco use and alcoho! consumption. The key word here is patient empowerment. | greatly welcome this guideline into the growing family of CPGs in the management of non-communicable diseases. Guidelines such as this are important decision support tools, not only for doctors, but for all health professionals involved in the management of patients with cardiovascular diseases. | would like to thank all of those involved for their time and energy in developing this guideline. However, the publication of this guideline is only the first step. | strongly urge concrete steps be taken to disseminate the information contained in this guideline and to monitor the effectiveness of its implementation in Malaysia. Thank you. Dato’ Sri Dr, Hasan Bin Abdul Rahman Director General of Health, MalaysiaMEMBERS OF THE EXPERT PANEL, CHAIRPERSON Dr. Azani Mohd Daud Consultant Cardiologist Gleneagles Intan Medical Centre Wilayah Persekutuan MEMBERS (In alphabetical order) Dr. Abd Kahar Ghapar Consultant Cardiologist Hospital Serdang Selangor Dr. Betty Teh Consultant Cardiologist Sime Darby Medical Centre Selangor Dr. Choo Gim Hooi Consultant Cardiologist KPJ Selangor Specialist Hospital Selangor Dr. Haizal Haron Kamar Consultant Cardiologist Tropicana Medical Centre Selangor Dr. K. Sree Raman Senior Consultant Physician Hospital Tuanku Ja’afar Seremban Negeri Sembilan Dr. Oteh Maskon Consultant Cardiologist University Kebangsaan Malaysia Medical Centre Wilayah Persekutuan Dr. Shaiful Azmi Yahaya Consultant Cardiologist Institut Jantung Negara Wilayah Persekutuan Dr. Tong Seng Fah Consultant Family Physician Department of Family Medicine University Kebangsaan Malaysia Medical Centre Wilayah PersekutuanEXTERNAL REVIEWERS (in alphabetical order) The following external reviewers provided feedback on the draft. Dr. Alzamani Mohammad Idrose Emergency Physician Hospital Kuala Lumpur Wilayah Persekutuan Dr. Aris Chandran Senior Consultant Physician Hospital Ipoh Perak Basariah Naina Pharmacist Hospital Kuala Lumpur Wilayah Persekutuan Dr. Chen Wei Seng Family Physician Klinik Alam Medic Selangor Dr. Chew Boon How Senior Medical Lecturer, Department of Family Medicine Faculty of Medicine and Health Sciences University Putra Malaysia Selangor Dr. Kauthaman A. Mahendran Senior Consultant Physician Hospital Melaka Melaka Dr. Jeyamalar Rajadurai Consultant Cardiologist Sime Darby Medical Centre Selangor Nurul Zaidah Badarudin Pharmacist Serdang Hospital Wilayah Persekutuan Dr. Shaiful Bahari Ismail Consultant Family Physician Hospital Universiti Sains Malaysia KelantanDr. Sim Kui Hian Consultant Cardiologist Sarawak General Hospital Sarawak Subramaniam Vatham Mudali Chairman, Persatuan Diabetes Malaysia Negeri Sembilan Dr. Wan Azman Wan Ahmad Consultant Cardiologist University Medical Malaya Centre Selangor Dr. Venugopal Balchand Consultant Cardiothoracic Surgeon Institut Jantung Negara Wilayah Persekutuan Dr. Zurkurnai Yusof Consultant Cardiologist Hospital Universiti Sains Malaysia KelantanRATIONALE AND PROCESS OF GUIDELINE DEVELOPMENT Rationale Coronary artery disease (CAD) comprises a broad spectrum of manifestation ranging from asymptomatic atherosclerosis to stable angina pectoris (SAP), acute coronary syndrome (ACS), myocardial infarction (MI) and congestive heart failure (CHF). The management of SAP has not been extensively studied in large randomised clinical trials, In Malaysia, these patients may be managed by cardiologists, physicians and primary care doctors. The CPG on Management of SAP was developed to help guide clinicians in the management of this group of patients. No previous guideline was available in Malaysia prior to this. Process This CPG was initiated by the National Heart Association of Malaysia (NHAM) in collaboration with the Academy of Medicine Malaysia (AM) and Ministry of Health Malaysia (MOH). The guideline committee consisted of cardiologists, physicians and primary care physicians from the government hospitals, universities and private hospitals. This CPG was adapted from the European Society of Cardiology (ESC) Guidelines on the Management of Stable Angina, 2006. The CPG was evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) prior to adaptation. Further evidence was evaluated from relevant publications from January 2006 through December 2009. Literature search was carried out at the electronic databases of PUBMED/ MEDLINE, Cochrane Databases of Systemic Reviews (CDSR), journal full text via OVID search engine. Refer to Appendix 3 for the terms used to retrieve articles. Reference was also made to other guidelines on the management of stable angina pectoris including The American College of Cardiology (ACC)/American Heart Association (AHA) 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina; European Society of Cardiology (ESC) Guidelines on the Management of Stable Angina, 2006; ACC/AHA guidelines for the clinical application of echocardiography, 1997; European guidelines on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts), 2007; American Diabetes Association, Standards of Medical Care in Diabetes, 2008; Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel Ill guidelines, 2004; ACC/AHA guidelines of percutaneous coronary interventions, 2001. Malaysia CPG on management of Type 2 Diabetes Mellitus, 2009; Malaysia CPG on Prevention of Cardiovascular Disease in Woman, 2008; Malaysia Consensus statement from on the utilization of cardiac CT, 2008; Malaysia CPG on Management of Acute ST Segment Elevation Myocardial Infarction (STEMI), 2007; Malaysia Medical Nutritional Therapy Guidelines for Hyperlipidaemia and Hypertension, 2005; Malaysia CPG on Management ofObesity, 2004; Malaysia CPG on Treatment of Tobacco Use and Dependence, 2003; Malaysia Clinical Practice Guidelines on Dyslipidaemia, 2003; Malaysia CPG of UA/NSTEMI, 2002; Malaysia CPG on Erectile Dysfunction, 2000; Malaysia Guidelines for Medical Practitioners performing medical examinations for vocational licence (PSV and GDL). In addition, the reference lists of all relevant retrieved articles as well as the reference list of the other guidelines reviewed were used to identify further studies. All relevant information was discussed thoroughly over several meetings before a draft guideline was prepared. The draft was submitted to the Technical Advisory Committee for Clinical Practice Guidelines, as well as the Health Technology Assessment (HTA) and Clinical Practice Guidelines Council, MOH Malaysia for review and approval. This was then submitted to a group of external reviewers selected from MOH hospitals, academic institutions as well as the private sector. Objectives These guidelines are intended to provide education and awareness on ways to: 1, Identify patients with stable angina 2, Assess, risk stratify and manage these patients appropriately Clinical Questions The clinical questions addressed in these guidelines include: . How does one diagnose a patient with SAP and exclude patient with unstable angina? . Having identified patients with SAP, what appropriate tests should be done for diagnosis and prognostication? Which patients should be referred for invasive procedures? . What appropriate treatment modalities, either non-pharmacological and/or pharmacological to be utilised? i) Be Target Group This guideline is directed at all healthcare providers treating SAP — general practitioners, medical officers, general and family physicians and cardiologists. Target Population This guideline is for the management of patients with Stable Angina Pectoris. It excludes patients with new-onset angina, crescendo angina and rest angina. Applicability The recommendations outlined are very much dependant on local expertise and availability of resources and does not apply universally to all healthcare providers. Factors which need to be taken into consideration at the local level in applying these recommendations include: 1. Organizational barriers 2. Cost implicationsExpected Benefits It is hoped that with appropriate usage of these guidelines, only those patients in whom there is general agreement will benefit from invasive management strategies will be referred to tertiary cardiac centres for further care whereas those patients who can be safely and adequately managed conservatively utilising management options outlined within these guidelines will continue in the care of their appropriate healthcare providers. Criteria for Monitoring/Audit Purposes The algorithm in Figure 1 is suggested to be used as a Clinical pathway for evaluation of patients with SAP. Patients identified as SAP patients may be audited against this pathway to see whether the processes in diagnosing and managing these patients are adhered to. The detailed appropriate processes will need to be determined within the local setting e.g. with respect to appropriate stress testing modality. Therapeutic options also make excellent criteria for audit purposes e.g. proportion of patients given adequate advice and monitored for non-pharmacological (lifestyle) intervention and use of appropriate pharmacological agents within local setting. Dr. Azani Mohd Daud ChairpersonGRADES OF RECOMMENDATIONS AND LEVELS OF EVIDENCE lla IIb. i i i [WE * CLINICAL PRACTICE © Grades of Recommendation Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful and/or effective Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure/therapy Weight of evidence/opinion is in favor of its usefulness/ efficacy Usefulness/efficacy is less well established by evidence/ opinion 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 Data derived from multiple randomised clinical trials or meta analyses Data derived from a single randomised clinical trial or large non randomised studies Only consensus of opinions of experts, case studies or standard of care LEVELS OF EVIDENCE Adapted from the American Heart Association (AHA) and the European Society of Cardiology (ESC)In general, processes within this red box can most Ikely be undertaken by primary care physicians if required. Diagnosis ~ \ Manage accordingly NO ischaemia Prognosis a» jinal chest pain” Suspected stable angina | Chest pain \ CLINICAL EVALUATION 1. History 2.ECG 3. Basic investigations __ Suspected UA/ACS _ \ Refer to CPG on ; UA/NSTEMI & GPG on Assessment of ischaemia Management of Acute ST- 1. Stress ECG and or ‘Segment-Elevation 2. Stress imaging 0 |... | Myocardial infarction _{PharmacologicaVExercise) } (sTeMi) 2007, 2” edition | ischaemia Confirmed stable angina on basis of clinical evaluation and non-invasive tests Intermediate risk High risk Medical therapy + Coronary arteriography Medical therapy AND Coronary arteriography "Refer to Table 4 Figure 7, Algorithm for the initial evaluation of patients with clinical symptoms of angina,TABLE OF CONTENT Statement of Intent ..,. Message from the Director General of Health, Malaysia Members of Expert Panel List of External Reviewers... Rationale and Process of Guidelines Development Grades of Recommendation and Levels of Evidence Algorithm for the initial evaluation of patients with Clinical symptoms Of ANGINA ..........-.2-+ceesescsesesereseereeseeesesseneeetenes Table of Content ... . INTRODUCTION . 2. DEFINITION AND PATHOPHYSIOLOGY . 2.1 Definition ..... 2.2 Pathophysiology . 3. PROGNOSIS ........ 4. DIAGNOSIS AND ASSESSMENT 4.1 Symptoms and Signs 4.2 Laboratory Tests... 4.3 Chest X-RAY (CXR) 4.4 Non-invasive Cardiac Investigations... 4.4.1 Resting Electrocardiography ECG) 4.4.2 Exercise stress testing .- aie 4.4.3 Stress testing in combination with imaging .. 4.4.3.1 Exercise testing with echocardiography 4.4.3.2 Exercise testing with myocardial eatusion scintigraphy .. aregnan ata 4.4.4 Pharmacological stress testing with imaging techniques 4.4.5 Stress Cardiac Magnetic Resonance (CMR) - 4.4.6 Echocardiography (Echo) at rest .. 4.4.7 Ambulatory Electrocardiographic (ECG) monitoring... 4.5 Non-invasive Techniques to Assess Coronary Calcification and Coronary Anatomy... 4.5.1 Electron Beam Computed Tomography (EBCT) 4.5.2 Multislice Computed Tomography (MSCT) ... 4.5.3 Cardiac Magnetic Resonance (CMR) ........ 4.6 Invasive Techniques to Assess Coronary Anatomy. 4.6.1 Coronary angiography .. 5. RISK STRATIFICATION .. 5.1 Clinical Evaluation 5.1.1 Clinical history 5.1.2 Physical examination 5.2 Resting ECG 5.3 Stress Testing 5.3.1 Exercise stress tes 5.3.2 Stress Echocardiography (Echo) ©5.3.3 Pharmacological stress echocardiography « 5.3.4 Stress perfusion scintigraphy -.. 5.3.5 Stress Cardiac Magnetic Resonance (CMR) 5.4 Ventricular Function 5.5 Coronary Arteriography 6. TREATMENT ..... 6.1 Aims of Treatment . 6.2 General Management 6.2.1 Lifestyle Modification . 6.2.1.1 Smoking cessation 6.2.1.2 Dietary control and fibre intake .. 6.2.1.3 Alcohol restriction 6.2.1.4 Physical activity. 6.2.2 Health Supplements .. 6.2.2.1 Omega-3 fatty acids 6.2.2.2 Vitamins, anti-oxidants and other health supplements 6.2.3 Others .. 6.2.3.1 Psychological factors 6.2.3.4 Heavy vehicle driving 6.2.4 Hypertension (HPT), Diabetes Mellitus (OM) and other disorder . 6.3 Pharmacological Treatment of Stable Angina Pectoris (SAP) 6.3.1 Acute treatment ... 6.3.2 Long-term treatment 6.3.2.1 Anti-thrombotic agents 6.3.2.1.1 Low dose aspi 6.3.2.1.2 Thienopyridines 6.3.2.1.3 Other anti-thrombotic agents 6.3.2.2 Lipid lowering therapy... 6.3.2.3 ACE-Inhibitors (ACEls).. 6.3.2.4 Angiotensin Receptor Blockers (ARBs) 6.3.2.5 Heart rate (HR) reducing agents 6.3.2.5.1 Beta-blockers 6.3.2.5.2 lvabradine .. 6,3.2.5.3 Non-dihydropyridine Calcium Channel Blockers (CCBs) . 6.3.2.6 Calcium Channel Blockers (CCBs) .. r 6.3.2.6.1 Dihydropyridine Calcium Channel Blockers (CCBs) .. ceased 6.3.2.6.2 Non-dihydropyridine Calcium Channel Blockers (CCBs) . 6.3.2.8 Trimetazidine 6.3.3 Other medical therapy 6.3.3.1 NSAIDs and COX 2 inhibitors 29 29 29 30 31 316.4 Myocardial Revascularisation ... 6.4.1 Percutaneous Coronary Intervention (Pcl) 6.4.2 Coronary Artery Bypass Grafting (CABG) ... 6.4.3 Percutaneous Coronary Intervention (PCI) versus Coronary Artery Bypass Grafting (CABG) . 6.4.4 Revascularisation versus medical therapy. 6.5 Special Subgroups . 6.5.1 Women 6.5.1.1 Clinical evaluation 6.5.1,2 Diagnosis 6.5.1.2.1 Clinical evaluation . 6.5.1.2.2 Stress testing .. 6.5.1.3 Treatment.. 6.5.2 Diabetes Mellitus (DM) 6.5.3 Elderly .. 6.5.3.1 Exercise stress ECG in the elderly 6.5.3.2 Coronary angiography 6.5.3,3 Treatment .... 6.5.4 Chronic refractory angina REFERENCES APPENDIX 1 APPENDIX 2 APPENDIX 3 ABBREVIATIONS ACRONYMS ... ACKNOWLEDGMENT . STATEMENT OF DISCLOSURE SOURCES OF FUNDING .... 31 32 32 32 33 34 34 34 34 34 34 35 35 36 36 36 36 36 38 58 59 60 61 63 64 64 641. INTRODUCTION Coronary Artery Disease (CAD) comprises a broad spectrum of manifestations ranging from asymptomatic atherosclerosis to symptomatic stable angina, acute coronary syndrome (ACS) and congestive heart failure (CHF). Local data for the prevalence of patients with SAP is not available. However in 2008, cardiovascular disease (CVD) was the commonest cause of death in MOH hospitals at 25.19% of total deaths.’ Data from USA shows that SAP is the initial presenting manifestation in approximately half of patients with CAD.** Reported annual incidence of angina is 213 per 100,000 population greater than 30 years old.” Annual incidence of uncomplicated angina pectoris in western population aged > 40 years is approximately 0.5% with geographic variations $+ Prevalence of angina varies according to sex and age ranging from 0.1 - 1% in women aged 45 - 54 years, 10 - 15% in women aged 65 - 74 years to 2 - 5% in men aged 45 - 54 years and 10 - 20% in men aged 65 - 74 years.""* The management of SAP has not been extensively studied with large Randomised Clinical Trials (RCT) as other parts of the disease spectrum thereby hampering efforts to define an optimum strategy for management of SAP. 2. DEFINITION AND PATHOPHYSIOLOGY 2.1 DEFINITION ANGINA Clinical syndrome characterised by: * Discomfort in chest, jaw, shoulder, back or arms * Typically aggravated by exertion or emotional stress * Relieved by rest or nitroglycerin (GTN) Unstable Angina (UA) may present in the following ways:”* Table 1. Presentation of UA Type Description Rest angina Pain of characteristic nature and location, but occurring at rest and for prolonged periods, up to 20 mins Crescendo angina Previously stable angina, which progressively increases in severity, intensity, and at lower threshold over a short period of 4 weeks or less New-onset angina Recent onset of severe angina, such that the patient experiences marked limitation of ordinary activity within 2 months of initial presentationThis CPG is a guide for the management of patients with angina who do not fulfill the criteria of UA. 2.2 PATHOPHYSIOLOGY The syndrome is attributed to myocardial ischaemia, the most common cause being atherosclerotic CAD. Other causes of myocardial ischaemia include: * Hypertrophic cardiomyopathy * Aortic stenosis * Coronary vasospasm * Coronary vasculitis from connective tissue disease * Aortic aneurysms * Coronary artery anomalies * Anemia Myocardial ischaemia is caused by an imbalance between myocardial oxygen supply and demand. Coronary arterial flow which is dependant on luminal cross-sectional area and arteriolar tone, is a major determinant of myocardial oxygen supply. Mismatch in myocardial oxygen supply and demand results in metabolic abnormalities, regional or global myocardial dysfunction, ECG changes and angina. In SAP, angina threshold may vary from day to day or even within the same day. Table 2. Canadian Cardiovascular Society Classification (CCS) of Angina ’ - P ‘ Limitation of Class — Severity of exertional stress inducing angina ordinary entlvity | Strenuous, rapid or prolonged exertion at None work or recreation " Walking or climbing stairs rapidly, walking Slight uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the few hours after awakening Ml Walking one or two blocks on the level Marked and climbing one flight of stairs in normal conditions and at a normal pace IV Inability to carry out any physical activity Discomfort in all without discomfort or symptoms may be _ activity performed present at rest Patients with SAP may become unstable. UA is characterised by angina which may be more prolonged, more frequent, more severe, occurring at a lower threshold or at rest” and patients may progress to non-ST-elevation or ST- elevation MI. (Formanagement of UA or MI, please refer to the Malaysia Clinical Practice Guidelines on UA/NSTEMF' and Clinical Practice Guidelines on Management of Acute ST Segment Elevation Myocardial Infarction (STEMI) 2007”) 3. PROGNOSIS European data estimates CAD mortality rates for men of 17.6 per 1,000 patient- years between age 70s and 90s."*% In the Framingham Heart Study, 2-year incidence rates for non-fatal MI and CAD death were 14.3% and 5.5% in men and 6.2% and 3.8% in women, respectively. Annual mortality rates from clinical trials on anti-anginal therapies and/or revascularisation ranges between 0.9 - 1.4%.” However, the prognosis for each Patient may vary considerably and the individual prognostic assessment is an integral part of management of patients with SAP. 4. DIAGNOSIS AND ASSESSMENT © Diagnosis and assessment of angina involves clinical assessment, laboratory tests, and specific cardiac investigations. In practice, diagnostic and prognostic assessments are conducted in tandem rather than separately, and many of the investigations used for diagnosis also offer prognostic information. * Analgorithm for the initial evaluation of patients presenting with clinical symptoms. suggestive of angina is depicted in Figure 1 (Page X). 4.1 SYMPTOMS AND SIGNS * A careful history alone may be enough for the diagnosis of angina pectoris, and confirmation is made by physical examination and objective tests. * The characteristics of discomfort related to myocardial ischaemia (angina pectoris) may be divided into four categories, summarised in Table 3 below: Table 3. The characteristics of discomfort related to myocardial ischaemia (angina pectoris) Characteristics Examples Location Classically retrosternal, but may be felt anywhere from the epigastrium tothe jaw or teeth, between the shoulder blades or in either arm to the wrist and fingers. Character Pressure, tightness, or heaviness, sometimes strangling, constricting, or burning. The severity of the discomfort varies greatly and is not related to the severity of the underlying coronary disease. Shortness of breath may accompany angina. Duration Not more than 10 minutes in the majority of cases Exacerbating Symptoms classically get worse with increased levels and relieving of exertion, and rapidly disappear at rest within a few factors minutes, Exacerbations of symptoms after a heavy meal, during emotional stress or first thing in the morning are features of angina. Sublingual nitrates may rapidly relieve angina.Definitions of typical and atypical angina have been previously published® and are summarised in Table 4. Table 4. Clinical classification of chest pain Type Characteristics Typical angina (definite) Meets three of the following characteristics * Retrosternal chest discomfort of characteristic quality and duration * Provoked by exertion or emotional stress * Relieved by rest and/or GTN Atypical angina Meets two of the above characteristics (probable) Non-cardiac chest pain Meets one or none of the above characteristics Non-anginal pain lacks the characteristic qualities described above and non- cardiac causes of pain should be evaluated in such cases. Table 5. Causes of non-anginal chest pain Underlying cause System Specific condition involvement Gastrointestinal Gastro-oesophageal reflux system Peptic ulcer disease Oesophageal spasm Gallstones Respiratory Pleurisy Non-cardiovascular system Pneumothorax Pulmonary embolism Pneumonia Neurology Neuralgia Psychiatry Psychosomatic Musculoskeletal Costochondritis Myalgia Cardiovascular Cardiac. Mitral valve prolapse (not myocardial Pericarditis ischaemia) Non-cardiac Aortic dissection Unstable Angina (UA) * It is important when taking the history to identify those patients with UA UA may present in one of three ways as defined in Table 1The investigation and management of suspected UA are dealt within the guidelines for the management of ACS. (For management of ACS, please refer to the Malaysia Clinical Practice Guidelines on Management of Acute ST Segment Elevation Myocardial Infarction (STEMI) 2007”) Physical examination is directed at: * looking for complications of CAD such as murmurs indicating mitral valvular regurgitation, septal defects, signs of cardiomegaly and CHF other sites of atherosclerosis — carotid bruits, peripheral vascular disease, aortic aneurysms ¢ risk factors for atherosclerosis such as hypertension, metabolic syndrome, etc. * other causes of angina such as hypertrophic obstructive cardiomyopathy (HOCM), aortic stenosis Investigations in stable angina may be divided broadly into 5 groups: 4.2 Laboratory tests 4.3 Chest X-Ray (CXR) 4.4 Non-invasive Cardiac Investigations 4.4.1 Resting Electrocardiography (ECG) 4.4.2 Exercise stress testing 4.4.3 Stress testing in combination with imaging 4.4.3.1 Exercise testing with echocardiography 4.4.3.2 Exercise testing with myocardial perfusion scintigraphy 4.4.4 Pharmacological stress testing with imaging techniques 4.4.5 Stress Cardiac Magnetic Resonance (CMR) 4.4.6 Echocardiography (Echo) at rest 4.4.7 Ambulatory Electrocardiography (ECG) monitoring 4.5 Non-invasive Techniques to Assess Coronary Calcification and Coronary Anatomy 4.6 Invasive Techniques to Assess Coronary Anatomy 4.2 LABORATORY TESTS The objectives of laboratory investigations are to: * establish cardiovascular (CV) risk factors (e.g. fasting glucose level fasting lipid profile,>*” homocysteine,” Lp(a), ApoA,** ApoB” * provide information relating to possible causes of ischaemia (e.g. haemoglobin level) * determine prognosis (e.g. hs-CRP,***:* serum creatinine*) " Recommendation of laboratory investigations j Fasting glucose — aes RP, homocysteine, La), APOA, ApoB Ub, B4.3 CHEST X-RAY (CXR) * In SAP, the CXR does not provide specific information for diagnosis or for risk stratification * The test should be requested only in patients with suspected CHF,“ valvular disease, or pulmonary disease® © The presence of cardiomegaly, pulmonary congestion, atrial enlargement, and cardiac calcifications have been related to prognosis**** Recommendations for CXR for initial diagnostic assessment of angina _ CXR in patients with clinical evide _ pulmonary disease 4.4 NON-INVASIVE CARDIAC INVESTIGATIONS This section describes investigations used in the assessment of angina and concentrate on recommendations for their use in diagnosis and evaluation of efficacy of treatment, whereas recommendations for risk stratification will be dealt with in the following section. 4.4.1 Resting Electrocardiography (ECG) * All patients with suspected angina pectoris based on symptoms should have aresting 12-lead ECG recorded * Aresting ECG may show evidences of CAD such as previous MI or an abnormal repolarisation pattern * Anormal resting ECG does NOT exclude the diagnosis of ischaemia * The ECG may assist in clarifying the differential diagnosis if taken in the presence of pain such as in vasospasm, allowing detection of dynamic ST-segment changes in the presence of ischaemia, or by identifying features of pericardial disease. * The ECG may also show other abnormalities such as left ventricular hypertrophy (LVH), bundle branch block, pre-excitation, arrhythmias, or conduction defects. © Such information may be helpful in defining the mechanisms responsible for chest pain, in selecting appropriate further investigation or in tailoring individual patient treatment. Recommendations for resting ECG for initial diagnostic assessment of angina Resting ECG during episode of pain (if possible) 1B "Recommendations for resting ECG for routine re-assessment in patients with SAP4.4.2 Exercise sirass testing * Anexercise test should be carried out only after careful clinical evaluation of symptoms and a physical examination including resting ECG * Exercise ECG is more sensitive and specific than rest ECG for detecting myocardial ischaemia’ * Exercise ECG should not be carried out routinely in patients with known severe aortic stenosis or hypertrophic cardiomyopathy © Interpretation of the exercise ECG test should be based on the pre-test probability of disease""” »* Exercise ECG testing is not of diagnostic value in the presence of © Left bundle branch block (LBBB) © Paced rhythm © Wolff-Parkinson-White (WPW) syndrome * The reasons for stopping the test are listed in Table 6 * In some patients, the exercise ECG may be non-conclusive if: © atleast 85% of maximum heart rate (HR) is not achieved in the absence of symptoms or ischaemia © exercise is limited by orthopaedic or other non-cardiac problems 0 ECG changes are equivocal * Inconclusive exercise test should then be followed by an alternative non-invasive diagnostic test, unless the patient has a very low pre-test probability (< 10%) of disease * For diagnostic purposes, the test should be conducted in patients without taking anti-ischaemic drugs provided it is safe to do so. * Exercise stress testing can also be useful to evaluate the efficacy of treatment after control of angina with medical treatment or revascularisation or to assist prescription of exercise after control of symptoms. © The effect of routine periodical exercise testing on patient outcomes has not been formally evaluated * False positive results are more frequent in patients with abnormal resting ECG, in the presence of LVH, electrolyte imbalance, intraventricular conduction abnormalities, and use of digitalis « Exercise ECG testing is also less sensitive and specific in women®Table 6. Reasons for terminating exercise stress test’? Reasons Examples Symptom limitation Pain, fatigue, dyspnoea, and claudication Combination Pain with significant ST-changes (symptoms and ECG) Safety reasons - Marked ST-depression (> 2 mm as relative indication for termination and = 4 mm as an absolute indication to stop the test) - ST-elevation > 1 mm - Significant arrhythmia - Sustained fall in systolic blood pressure (SBP) > 10 mmHg - Marked HPT (> 250 mmHg systolic or > 115 mmbg diastolic) Achievement of Decision to terminate the test is at the discretion maximum predicted HR _ of the physician Recommendations for exercise ECG for initial diagnostic assessment of angina Patients with angina and intermediate-to-high pre-test LB probability of CAD* unless unable to exercise or displays ECG changes which make ECG non-evaluable Patients with 2 1 mm ST-depression on resting ECG or IIb, B taking digoxin Patients with low pre-test probability (< 10%) of CAD® lb, B a = based on age, gender and symptoms, see appendix 1. Recommendations for exercise ECG for routine re-assessment in patients with SAP Routine periodic exercise ECG in the absence of clinical IIb, C change 4.4.3 Stress testing in combination with imaging * The most well-established stress imaging techniques are echo and perfusion scintigraphy and both may be used in combination with either exercise stress or pharmacological stress * Novel stress imaging techniques also include stress CMR, which, for logistical reasons, is most frequently performed using pharmacological stress rather than exercise stress* Stress imaging techniques have several advantages over conventional exercise EGG testing including superior diagnostic performance (Table 7) for the following reasons: © detection of obstructive CAD © the ability to quantify and localise areas of ischaemia © the ability to provide diagnostic information in the presence of resting ECG abnormalities © Stress imaging techniques are often preferred in patients with previous PCI or CABG* because of superiority in localising ischaemia * In patients with angiographically confirmed intermediate coronary lesions (60% - 70% stenosis on angiography), evidence of anatomically appropriate ischaemia is predictive of future events, whereas a negative stress imaging test can be used to define patients with a low cardiac risk, who can be reassured Table 7. Summary of test characteristics for investigations used in the diagnosis of SAP'® Diagnosis of CAD Sensitivity (%) Specificity (%) Exercise ECG 68 7 Exercise echo 80 - 85 84 - 86 Exercise myocardial perfusion 85 - 90 70-75 Dobutamine stress echo 40 - 100 62 - 100 Vasodilator stress echo 56 - 92 87 - 100 Vasodilator stress myocardial perfusion 83 -94 64-90 4.4.3.1 Exercise testing with echocardiography * Exercise stress echo is an alternative to ‘classical’ exercise testing with ECG and provides additional information to establish the presence or location and extent of myocardial ischaemia during stress * Aresting echocardiogram is acquired before a symptom-limited exercise test is performed with further image acquisition at peak exercise * Overall sensitivity and specificity of exercise echocardiography is 80 - 85% and 84 - 86% respectively" * Tissue Doppler and strain rate imaging are expected to improve the accuracy and reproducibility of stress echo in the broader clinical settin: 4.4.3.2 Exercise testing with myocardial perfusion scintigraphy * Thallium-201 and technetium-99m radiopharmaceuticals are the most commonly used tracers, employed with single-photon emission computed tomography (SPECT) in association with a symptom-limited exercise test on either a bicycle ergometer or a treadmill * It produces images of regional tracer uptake that reflects relative regional myocardial blood flow. Myocardial hypoperfusion is characterised by reduced tracer uptake during stress in comparison with uptake at rest * Itis more sensitive and specific than exercise ECG (Table 7) °4.4.4 Pharmacological stress testing with imaging techniques Pharmacological stress may also be employed when the use of exercise imaging is not possible Pharmacological stress testing with either perfusion scintigraphy or echocardiography is indicated in patients who are unable to exercise adequately or may be used as an alternative to exercise stress Two approaches may be used to achieve this: © infusion of short-acting sympathomimetic drugs (e.g. dobutamine)” © infusion of coronary vasodilators (e.g. adenosine and dipyridamole) The diagnostic performance of pharmacological stress perfusion and pharmacological stress echo is also similar to that of exercise imaging techniques (Table 7)" Stress imaging has an important role to play in evaluating patients with a low pre-test probability of disease, particularly women,’*” when exercise testing is inconclusive, in selecting lesions for revascularisation and in assessing ischaemia after revascularisation’*”” Recommendations for the use of exercise stress with imaging techniques (either echo or perfusion) in the initial diagnostic assessment of angina Patients with resting ECG abnormalities e.g. LBBB, > 1 mm ST- 1B depression, paced rhythm, or WPW which prevent accurate interpretation of ECG changes during stress Patients with a non-conclusive exercise ECG but reasonable. ,B exercise tolerance, who do not have a high probability of significant coronary disease and in whom the diagnosis is still in doubt Patients with prior revascularisation (PC! or CABG) in whom lla, B localisation of ischaemia is important As an alternative to exercise ECG in patients where lla, B facilities, costs, and personnel resources allow As an alternative to exercise ECG in patients with a low pre-test Ila, B probability of disease To assess functional severity of intermediate lesions on Na, C coronary arteriography To localise ischaemia when planning revascularisation lla, C options in patients who have already had arteriography Recommendations for the use of pharmacological stress with imaging techniques (either echo or perfusion) in the initial diagnostic assessment of angina Class |, lla, and IIb indications as mentioned earlier, if the patient is unable to exercise adequately4.4.5 Stress Cardiac Magnetic Resonance (CMR) * Stress CMR can be used to detect wall motion abnormalities induced by ischaemia or perfusion abnormalities * Stress CMR, using either perfusion imaging or stress-induced wall motion abnormalities imaging, demonstrates good sensitivity 83 - 91% and specificity 81 - 86% for the diagnosis of CAD.” High quality CMR perfusion has been shown to be at least as good as single photon emission computed tomography scan (SPECT) for the diagnosis of CAD. It also has a close correlation with invasive flow and pressure measurements.” * Dobutamine stress CMR has been shown to be superior to adenosine stress CMR to detect ischaemia in patients with suspected or known CAD but no history of prior MI? 4.4.6 Echocardiography (Echo) at rest * Two-dimensional and doppler echo is useful in patients with clinically detected murmurs," history and ECG changes compatible with hypertrophic cardiomyopathy®* or previous MI‘ and symptoms or signs of CHF® * Recent developments in tissue Doppler imaging and strain rate measurement have greatly improved the ability to study diastolic function®" Recommendations for echo for initial diagnostic assessment of angina Patients with suspected CHF IB Patients with LBBB, Q waves or other significant hc 4.4.7 Ambulatory Electrocardiographic (ECG) monitoring © Ambulatory ECG (Holter) monitoring may reveal evidence of myocardial ischaemia during normal ‘daily’ activities* * However, it rarely adds important diagnostic or prognostic information in chronic stable angina pectoris over and above that provided by an exercise test * It may have a role in patients in whom vasospastic angina is suspected ¢ In patients with SAP and suspected major arrhythmias, Holter monitoring is an important method of diagnosing arrhythmias _ Recommendations for ambulatory ECG for initial diagnostic "assessment of angina ' fame vasospastic angina lla, C4.5 NON-INVASIVE TECHNIQUES TO ASSESS CORONARY CALCIFICATION AND CORONARY ANATOMY There are 3 non-invasive modalities to define the coronary anatomy: 1. Electron beam computed tomography (EBCT) with/without angiogram 2. Multislice computed tomography (MSCT) angiogram 3. Cardiac magnetic resonance (CMR) 4.5.1 Electron Beam Computed Tomography (EBCT) The EBCT is effective in quantifying the extent of coronary calcification.” The coronary calcium score identifies a population at higher risk of significant coronary artery disease, and has been found to correlate well with overall burden of plaque.* However, due to low spatial resolution and high image noise, EBCT angiogram is not an appropriate diagnostic tool for patients with SAR” 4.5.2 Multislice Computed Tomography (MSCT) Cardiac CT is performed as a 2-part examination. Firstly, the coronary artery calcium score and secondly the coronary artery CT angiogram.” The use of MSCT angiogram allows good diagnosis, accurate detection and quantification of stenosis of major segments of right and left coronary arteries. The 64 slice detector CT angiogram has a negative predictive value of 93 - 99% and sensitivities and specificities of 90 - 94% and 95 - 97% respectively.'"'* _ Recommendations for the use of CT angiography in SAP : - Patients who disability, illness, 4.5.3 Cardiac Magnetic Resonance (CMR) CMR is an emerging modality for cardiac imaging. It is an excellent modality for evaluation of myocardial structure, function, reversible ischaemia and viability, however the current MRI technology has limited diagnostic accuracy for assessment of coronary stenosis.'* 4.6 INVASIVE TECHNIQUES TO ASSESS CORONARY ANATOMY 4.6.1 Coronary angiography Coronary angiography is defined as the radiographic visualisation of the coronary vessels after injection of radiopaque contrast media. Coronary angiography allows anatomical definition of the coronary arteries, degree of luminal obstruction and determination of prognosis. The risk of complications with routine angiogram is between 1 and 2% with the current methods.’* The composite rate of death, MI, or stroke is of the order of 0.1 - 0.2%.’Recommendations for coronary angiography for establishing a diagnosis of SAP Severe SAP (Class 3 or greater of CCS Classification), with a IB high pre-test probability of disease, especially if symptoms are not responding to medical treatment Survivors of cardiac arrest LB Patients with serious ventricular arrhythmias. ic Patients previously treated by myocardial revascularisation ,C (PCI, CABG) who develop early recurrence of moderate or severe angina pectoris Patients with an inconclusive diagnosis on non-invasive lla, C testing, or conflicting result from different non-invasive modalities at intermediate to high risk of coronary disease Patients with a high risk of restenosis after PCI if PCI has lla, C been done in a prognostically important site Patients who cannot undergo non-invasive testing due to lla, C disability, iliness, or morbid obesity Patients with a high pre-test probability of left main or lla, C 3-vessel CAD Patients with significant LV dysfunction (left ventricular lla, C ejection fraction (LVEF) < 45%), CCS class | or Il angina, and demonstrable ischaemia but less than high-risk criteria on non-invasive testing Patients with recurrent chest pain in whom a definite diagnosis __Ilb, C is judged necessary Patients with significant co-morbidity in whom the risk of M,C coronary arteriography outweighs the benefit of the procedure Adjunctive invasive techniques with coronary angiography for assessment of CAD include intravascular ultrasound (|VUS), fractional flow reserve (FFR) and coronary angioscopy. 5. RISK STRATIFICATION The process of risk stratification serves 2 purposes: * To provide information regarding prognosis * To assist in choosing appropriate treatment, e.g. revascularisation in high risk groups While clear risk stratification exists for primary prevention, absolute levels of what constitutes high risk and low risk are not clearly defined for those with established CVD. Risk stratification primarily refers to the risk of cardiovascular death. However, there is no systematic predictive method to determine what constitutes high risk or low risk."®"® The Euro heart angina score probably provides the simplest and most objective way to discriminate extremely low riskgroup and those at high risk. Comorbidity, diabetes, severity of angina, duration of symptoms, left ventricular function and ST segment changes on resting ECG independently predict outcome, i.e. non-fatal MI and death.'” For the purposes of these guidelines, an individual with SAP is deemed: * high risk - if he has annual CV mortality of > 2%" * intermediate risk - if he has annual CV mortality of 1 - 2% * low risk - if he has annual CV mortality of < 1%" Information required to stratify a patient’s risk: A. Clinical evaluation B. Non-invasive assessment of ischaemia C. Quantification of ventricular function D. Extent of CAD (angiography) 5.1 CLINICAL EVALUATION* ™. 105 110-112 5.1.1 Clinical history Important predictors of adverse outcome in patients with established CAD"; © DIM? 28. 118:116 © HP T2708. 16118 * Metabolic syndrome * Current smoker”°* "+1" * Increasing age“ © Prior MI‘ « Symptoms and signs of CHF*.6"? * Pattern of occurrence of angina (recent onset or progressive)" '” * Severity of angina, particularly if unresponsive to therapy" ” * Dyslipidaemia 5.1.2 Physical examination The presence of the following assists in determining risk: * peripheral vascular disease (PVD) - either lower limb or carotid" * signs related to CHF 5.2 RESTING ECG Resting ECG abnormalities can predict patients at greater risk of future CV events than those with a normal ECG.* °° The abnormalities are: * Evidence of prior MI ° LBBB * Left anterior hemiblock *°LVH * Second or third degree AV block * Atrial fibrillation (AF)5.3 STRESS TESTING ™ 1% 10112 Risk stratification using stress testing * Stress testing can be in the form of exercise or pharmacological stress, with or without imaging. * Prognostic information that can be obtained from stress testing: © detection of ischaemia © ischaemic threshold © extent and severity of ischaemia (for imaging techniques) © functional capacity (for exercise testing) * The choice of initial stress test should be based on the patient’s resting ECG, physical ability to perform exercise, local expertise, and available technologies. * Commonly used stress testing modalities are: 1. Exercise stress test 2. Stress echo 3. Stress perfusion scintigraphy 5.3.1 Exercise stress test * Prognostic exercise testing markers include exercise capacity and exercise- induced ischaemia (clinical and ECG). * Maximum exercise capacity is a consistent prognostic marker. It may be measured by © maximum exercise duration © maximum MET level achieved © maximum HR © double (rate-pressure) product * In patients with known CAD and normal or mildly impaired LV function, the 5- year survival is higher in patients with a better exercise tolerance.** © 117° * An early positive exercise test (ST depression > 1 mm within stage 1 or 2 of standard Bruce protocol) identifies a high risk population.” * The Duke treadmill score (DTS) is a well-validated score which combines exercise time, ST deviation, and angina during exercise to calculate the patient’s risk (Figure 2).'% Figure 2. DTS score.'?” Duke treadmill score Score a. Exercise time (in minutes) n b. ST-depression (mm x 5) -n cc. Angina (non-limiting) OR -4 d. Angina (limiting) -8 Total score =a +b + (COR d) Risk Total score 1-year mortality Low 25 0.25% Intermediate 4 to-10 1.25% High <-11 5.25%Recommendations for risk stratification according to exercise stress ECG in SAP in patients who can exercise All patients without significant resting ECG abnormalities iB undergoing initial evaluation Patients with stable coronary disease after a significant change |, C in symptom level Patients post-revascularisation with a significant deterioration lla, B in symptomatic status 5.3.2 Stress Echocardiography (Echo) * May be used to risk stratify patients at risk of CV events® "* * Has an excellent negative predictive value in patients with a negative test having an event rate (death or Ml) of < 0.5% per year!™.199 Risk of future events is influenced by the number of oO resting regional wall motion abnormalities © inducible wall motion abnormalities on stress echo® * Identification of a high risk cohort allows for appropriate further investigation and/or intervention Recommendations for risk stratification according to exercise stress imaging (perfusion or echo) in SAP in patients who can exercise Patients with resting ECG abnormalities e.g. LBBB, > 1 mm IC ST-depression, paced rhythm, or WPW which prevent accurate interpretation of ECG changes during stress Patients with a non-conclusive exercise ECG, but ,B intermediate or high probability of disease Patients with a deterioration in symptoms post- lla, B revascularisation As an alternative to exercise ECG in patients, in which lla, B facilities, cost, and personnel resources allow 5.3.3 Pharmacological stress echocardiography * Dobutamine and vasodilators (2.g. dipyridamole) at appropriately high doses are equally potent ischaemic stressors and have similar accuracies and specificities to exercise’ © The presence (or absence) of inducible wall motion abnormalities separates patients with different prognosis" "° * Normal stress echocardiogram yields a cardiac event risk of 0.4% to 0.9%" Recommendations for risk stratification according to pharmacological stress imaging (perfusion or echo) in SAP Patients who cannot exercise IB Other class | and II indications as for exercise stress imaging (perfusion or echocardiography) in SAP in patients who can exercise, but where local facilities do not include exercise imaging5.3.4 Stress perfusion scintigraphy * Normal stress myocardial perfusion images carries a benign prognosis, with an event rate of < 1% per year, which is nearly as low as that of the general population." © The only exceptions would appear to be patients with normal perfusion images with either a high-risk treadmill ECG score or severe resting LV dysfunction" In contrast, abnormal findings have been associated with severe CAD and subsequent cardiac events. « Large stress-induced perfusion defects, defects in multiple coronary artery territories, transient post-stress ischaemic LV dilatation, and in patients studied with thallium-201, increased lung uptake" on post-exercise or pharmacologic stress images are all adverse prognostic indicators." * * Exercise stress imaging offers greater prognostic information than pharmacological stress imaging because of the information regarding symptoms, exercise tolerance and haemodynamic response to exercise, which is additive to that obtained from perfusion or echo data alone. 5.3.5 Stress Cardiac Magnetic Resonance (CMR). *|n patients with known or suspected CAD, myocardial ischaemia detected by adenosine and dobutamine stress CMR can be used to identify patients at high risk for subsequent cardiac death or non-fatal MI. For those with normal stress CMR, the 3-year event-free survival was 99.2%."* * Adenosine stress CMR imaging is safe to perform early after acute STEMI and can identify patients with significant coronary stenosis more accurately than exercise stress test.” * Adenosine stress CMR may help to identify patients at risk who would benefit from intensified medical treatment and close follow-up." 5.4 VENTRICULAR FUNCTION. 16112 Risk stratification using ventricular function * Strongest predictor of long-term survival is LV function. * Prevalence of asymptomatic ventricular dysfunction has been reported to be as high as twice that of clinical CHF, with the presence of IHD a major risk factor for its occurrence.'""" In patients with SAP, as LVEF declines, mortality increases. * Resting LVEF of < 35% is associated with an annual mortality rate > 3% per year's 1.18 * An estimation of ventricular function is desirable in risk stratifying patients with SAP, and an assessment for ventricular hypertrophy (by echo or MRI) and of ventricular function is particularly pertinent in patients with HPT or DM. LVEF 12-year survival rate” (P< 0.0007) < 35% 21% 35-49% 54% > 50% 73%ee for risk stratification by echo. evaluation of ‘ventricular function in SAP_ tients with a normal resting ECG without lla, © ot others to be considered for coronary 5.5 CORONARY ARTERIOGRAPHY® *105,10-172 Risk stratification using coronary arteriography * Despite the recognised limitations of coronary arteriography to identify vulnerable plaques which are likely to lead to acute coronary events, the following have been convincingly demonstrated to be important prognostic indicators in patients with angina.“ "11% o extent of CAD (number of vessels involved) © severity of luminal obstruction © location of coronary disease (left main stem (LMS) and proximal left anterior descending artery (LAD) * In the CASS registry of medically treated patients, the 12-year survival rate of patients with normal coronary arteries was 91% compared with 74% for those with single vessel disease, 59% for those with two-vessel disease (2VD), and 50% for those with three-vessel disease (3VD) (P < 0.001). * The 5-year survival rate for patients with 3VD including a > 95% proximal LAD stenosis was 54% compared with a rate of 79% for patients with 3VD without LAD stenosis."* * The use of coronary arteriography to identify patients whose prognosis can be improved is likely to be appropriate in high but not low risk groups. * In the intermediate risk group, the decision should be guided by a variety of factors including the patient’s symptoms, functional status, lifestyle, occupation, co-morbidity, and response to initial medical therapy. * It is the duty of the physician to ensure that the patient is fully informed of their risk and the potential benefits or lack of benefit of any particular procedure and to guide their decision appropriately. * Coronary arteriography should NOT be performed in patients © with angina who refuse invasive procedures © who prefer to avoid revascularisation © who are not candidates for PCI or CABG 0 in whom PCI/CABG will not improve quality-of-lifeae alate gs coronary, arteriography in ‘evere SAP (Class 3 or greater of CCS Classification), particularly if "the ra seea fly responding to medical treatment sive , tac anos A summary of the recommendations for the routine use of investigations in the evaluation of SAP, with corresponding levels of evidence related to diagnosis and prognosis, is presented in Appendix 2. 6. TREATMENT 6.1 AIMS OF TREATMENT: Generally treatment is aimed to: * prevent MI and death ® minimise or abolish symptoms of angina thereby improving quality of life (QoL) 6.2 GENERAL MANAGEMENT Lifestyle modification should be emphasised to all patients with SAP in addition to pharmacological measures and revascularisation. Symptoms can be improved in most patients with appropriate measures. Upon comprehensive risk stratification (see section 5): * patients and close relatives should be well-informed of the nature and prognosis of the disease as well as the implication of the diagnosis * treatment goals and strategies should be discussed to improve compliance * lifestyle risks should be identified and managed accordingly 6.2.1 Lifestyle modification 6.2.1.1 Smoking cessation Smoking is strongly discouraged. This is the most important reversible risk factor. Smoking cessation greatly improves symptoms and prognosis. There was a 36% relative reduction in mortality and a 32% relative reduction in non-fatal MI for patients with CHD who quit smoking compared with those who continue to smoke."* Nicotine replacement therapy is safe and helpful."*” If possible, patient should be referred to centres with expertise in smoking cessation because a structured smoking cessation program has a higher success rate than brief office advice.Table 8 below provides the list of available nicotine replacement therapy available in Malaysia. Varenicline tartrate is now available and effective in smoking cessation. It has proven efficacy and safety in general population.‘ The same treatment regime is advocated for CAD patients.'”' However there has been some safety concerns by Food and Drug Administration in the United States regarding the risk of depression and suicidal thoughts. Clinicians may want to refer to Malaysia Clinical Practice Guidelines on Treatment of Tobacco Use and Dependence.” Table 8. Nicotine replacement therapy available in Malaysia’™ Nicotine Recommended Regime Replacement Therapy Nicotine gum * Use 2 mg gum for patients smoking less than 20 * Nicorette® 2 mg cigarettes per day *Nicorette® 4mg * Use 4 mg gum for patients smoking 20 or more cigarettes per day * Generally, the gum should be used for up to 12 weeks with no more than 24 pieces/day * Clinicians should tailor the dosage and duration of therapy to fit the needs of each patient Nicotine patch * Appiied on skin as soon as the patient wakes on 1. Nicorette® their quit day * Use 15 mg x 8 weeks, then 10 mg x 2 weeks and finally 5 mg x 2 weeks 2. Nicotinell® * Applied on skin as soon as the patient wakes © TTS10 (7 mg) on their quit day © TTS20 (14 mg) © For patient smokes > 20 cig/day, use: © TTS30 (21 mg) « TTS30 for 1 - 4 weeks « TTS20 for 5 - 8 weeks « TTS10 for 9 - 12 weeks * For patient smokes < 20 cig/day, use: « TTS20 for 1 - 4 weeks « TTS20 for 5 - 8 weeks « TTS10 for 9 - 12 weeks Nicotine inhaler * 6 - 16 cartridges/day up to 6 months of treatment (4 mg/cartridge) * Taper dosage during the final 3 months of treatment Varenicline * Day 1 - 3: 0.5 mg once daily tartrate * Day 4-7: 0.5 mg bd * Day 8 - end of treatment: 1 mg bd * Duration: 12 weeks. If successful stopped at 12 weeks, an additional course of 12 weeks treatment may be considered * Quit dateis set 1 - 2 weeks before taking varenicline6.2.1.2 Dietary control and fibre intake Dietary intervention is an effective adjunct measure if properly implemented.” 1 Healthy eating and appropriate dietary intervention have favourable effects on many CAD risk factors” notably HPT, hypercholesterolaemia, obesity and DM. Patients should be encouraged to adopt a healthy eating habit,” which includes * Eating a variety of fruits, vegetables, legumes, nuts, soy products, low-fat dairy products, and whole grain breads, cereals and pastas * Minimising the intake of foods high in saturated and trans-fats, such as red meat, whole milk products, and pastries Polyunsaturated fat is preferable to monounsaturated fat because it is associated with lower CV mortality in patients after MI.'’””"”® However, there has been no direct study on patients with stable CAD. Food high in polyunsaturated fat include: * oily fish * walnuts * sesame and pumpkin seeds * vegetable oils such as sunflower oil The intensity of dietary changes is guided by abnormality of patients’ lipid profile, weight, DM and blood pressure (BP) control. An ideal body weight and waist circumference should be aimed for if achievable with appropriate calorie intake. Clinicians may want to refer to the respective clinical practice guidelines for CV tisk factors management. Table 9. Targets for BMI"? Group BMI (kg/m?) Risk of co-morbidities Underweight < 18.5 Low (but increased risk of other clinical problems) Ideal 18.5 - 22.9 Average: target for BMI Pre-obese 23,0- 27.4 Increased Obese! 27.5-34.9 Moderate Obese Il 35.0- 39.9 Severe Obese Ill > 40.0 Very severe Targets for waist circumference (Malaysia Clinical Practice Guideline Clinical Practice Guidelines on Management of Obesity, 2003): * Men < 85 cm * Women < 80cm Increase intake of soluble fibres is encouraged because it has been shown to have asmall but significant reduction in total cholesterol and LDL cholesterol level in meta-analysis among healthy subjects and high risk patients for CAD." Soluble fibre is found in oats, peas, beans, legumes (dhall, chickpeas, red beans andgreen beans), apples, citrus fruits, carrots, and barley. High fibre intake was also associated with reduced risk of MI and death from CAD in cohort studies among healthy subjects.'* '® Patients should be advised to increase total fibre intake by including 3 servings of vegetables and 2 servings of fruits daily. They should also increase whole grains such as brown rice, whole wheat breads and chapatti."* The benefit of soluble fibres should not be denied for patients with stable CAD despite insufficient evidence on the benefit of increasing fibre intake among patients with CAD. 6.2.1.3 Alcohol restriction Alcohol intake at moderation may be beneficial in reducing the population risk of CV events.’ There is insufficient evidence to recommend alcohol consumption among patients with stable CAD. It is also generally difficult to quantify units of alcohol intake by general public.” 6.2.1.4 Physical activi Patients should be encouraged to engage in physical activities within their limits. The minimal goal should be 30 mins, 3 - 4 days per week. Moderate intensity aerobic activities are recommended e.g. brisk walking. Physical activity is beneficial on weight reduction, BP control, lipid abnormalities, glucose tolerance and insulin sensitivity. Several randomised control trials and meta-analysis have demonstrated improvement in mortality, symptoms and exercise tolerance with exercise programs. 1%" Regular exercise is recommended, but individual fitness and severity of symptoms should be taking into consideration. Exercise stress test can assist in prescription of an appropriate exercise program. _ Recommendations for lifestyle modification = = Dietary control & fibre intakes '* Healthy dietary choices 1B '* Use of polyunsaturated fat 4c _ © Fibre intake CG ‘ Physical activity 30 mins 3 - 4 days per week LA 6.2.2 Health supplements 6.2.2.1 Omega-3 fatty acids Omega-3 fatty acids are generally found in fish oil. Epidemiological studies in the populations showed that men who ate at least some fish weekly had a lower CAD mortality than men who ate none." Large control trials using up to 1g of omega- 3 fatty acids daily reduced the risk of sudden death in patients with recent MI." '** However, there is no clear evidence of benefit among stable CAD patients."6.2.2.2 Vitamins, anti-oxidants and other health supplements Generally the use of vitamins, anti-oxidants, garlic and co-enzyme Q10 for stable CAD patient is not encouraged." There is generally lack of evidence for CV mortality benefit from these supplements. Morbidity benefit from co-enzyme Q10 was shown only among patients with CHF. ; for health supplements — — - Recomment 6.2.3 Others 6.2.3.1 Psychological factors Diagnosis of CAD often leads to excessive anxiety and depressions.'* '® Psychological factors may provoke attacks of angina and are associated with a higher risk of coronary mortality.'°”1 Anxiety and depression should be actively screened for and treated. Cardiac rehabilitation and self-management empowerment has been shown to improve psychological, physical symptoms and functional status.” The patients should be properly educated on: * Characteristic of their disease * Personal risk factors * Therapeutic lifestyle changes to address the risk factors * Treatment goals and prognosis * Action plan during an anginal attack 6.2.3.2 Sexual acti Sexual activity is no more stressful to the heart than a number of other natural daily activities e.g. walking one mile (1.6 km) on the level in 20 minutes (Table 28). Patients who can engage in activities requiring METs score rating between 3 - 4 can safely resume non vigorous sexual activities because they have low cardiac risk. Patients who do not fulfill this criterion should be referred for further assessment by a specialist. Sexual intercourse may trigger angina. GTN may be helpful prior to intercourse. Phosphodiesterase-5 (PDE-5) inhibitors can be prescribed safely*":** but should not be used in those receiving any nitrates. Table 9. METs score rating of some daily activities™ Daily activity METs Score Rating ‘Sexual intercourse with regular partner * lower range (“normal”) * upper range (vigorous activity) Lifting and carrying objects (9 - 20 kg) Walking one mile in 20 minutes on the level Golf Gardening (digging) DIY, wallpapering, etc. Light housework (e.g. ironing, polishing) Heavy housework (e.g. making beds, scrubbing floors) OnrRORORaAN DRAAHTEABwICAL PR jw Witaine © And Beata RE ANC ER: 6.2.3.3 Employment Patient should be encouraged to continue their occupation with appropriate adjustment as necessary to avoid angina episodes. 6.2.3.4 Heavy vehicle driving Patients are prohibited to drive commercial public transport/heavy vehicles if they are symptomatic or suffer from complications of CAD like CHF and arrhythmias. 6.2.4 Hypertension (HPT), Diabetes Mellitus (DM) and other disorders Concomitant HPT, DM and other features of metabolic syndrome should be addressed as these are major risk factors to CAD.** The target BP for patients with CAD is < 130/80 mmHg.”” Beta-blockers, ACEIs™*2" and long acting CCBs,” are the drugs of choice. Pharmacological intervention is necessary if target is not achieved upon diagnosis. DM should be managed carefully with the target HbA1c < 6.5%.” The target level for HbA1c must be individualised based on risks of hypoglycaemia and quality of life 2.2" Hypoglycaemia must be avoided as it may precipitate anginal attack and increase mortality.”" Hypercholesterolaemia should be controlled to target (Table 10). Please refer to Clinical Practice Guidelines on Dyslipidaemia 2003.77 Table 10. Targets for cholesterol levels*”” Note: * In patients with triglyceride of > 2.3 mmol/l, a non-HDL cholesterol of <3.4 mmol/l should be aimed for. * It should be emphasised that LDL-cholesterol is the primary target of therapy. HDL-C and triglyceride are the secondary targets. Anaemia and hyperthyroidism, if present should be corrected.6.3 PHARMACOLOGICAL TREATMENT OF STABLE ANGINA PECTORIS (SAP) The goals of: 1. Acute treatment are: * Relieve symptoms = Prevent provocable angina 2. Long-term treatment are: * Improve prognosis (Reduction in CV events) * Improve QoL by reducing severity and frequency of anginal attacks 6.3.1 Acute treatment Self-management during an acute attack of angina: During an acute attack of angina, patient is advised to * rest and refrain from provoking activities * take sub-lingual/buccal GTN (tablet or spray) * sit in order to protect against potential harm of hypotension upon use of GTN and should be warned of possible side effect of headache Patient can be encouraged to use prophylactic GTN to prevent predictable episodes. Medical advice should be sought if symptoms persist > 10 minutes after resting and/or is not relieved by three GTN. 6.3.2 Long-term treatment Pharmacological strategies are: 6.3.2.1 Anti-thrombotic agents 6.3.2.1.1 Low dose Aspirin Aspirin inhibits COX-1 and thromboxane production and remains the main pharmacological prevention of arterial thrombosis. Use of low dose Aspirin (75 mg)** in stable angina and silent ischaemia are associated with lower Incidence of MI, cardiac death or stroke.7* Dosage of Aspirin should be the lowest effective to optimise the balance between therapeutic gains and gastrointestinal side effects during chronic therapy. The optimal anti-thrombotic dosage of aspirin appears to be 75 - 150 mg/day. The SAPAT trial showed a 34% reduction of MI or cardiac death with aspirin 75 mg/day compared with placebo in sotalol-treated patients with stable angina pectoris. 6.3.2.1.2 Thienopyridines Clopidogrel and Ticlopidine are thienopyridines which act as non competitive ADP receptor antagonist with similar antithrombolic effects of aspirin.” Clopidogrel Clopidogrel 75 mg daily is more effective compared to aspirin alone in preventing CV complication in high risk patient especially in the peripheral vascular disease arm." Combination of aspirin and Clopidogrel is not warranted in SAP.Ticlopidine Ticlopidine efficacy has been documented in stroke and PCI. However, there are no large clinical trials to support the use of Ticlopidine in SAP. Ticlopidine has 1 - 2% risk of neutropenia and thrombocytopenia and other symptomatic side effects. 6.3.2.1.3 Other anti-thrombotic agents Dipyridamole Dipyridamole is not recommended for anti-thrombotic treatment in SAP due to poor anti-thrombotic efficacy and the risk of worsening angina symptoms due to coronary steal phenomena.” Anticoagulation Anticoagulant drugs (warfarin or thrombin inhibitor) are not indicated in SAP without a separate indication such as AF. 6.3.2.2 Lowering Therapy Statin therapy has been shown to reduce CV events and mortality by 20 - 30%. There has been no statin trials specifically for patients with SAP. However, the HPS trial’ has shown a reduction in chest pain and the need for revascularisation in patients with stable CAD. These benefits were seen irrespective of age, gender and baseline LDL-C levels. Many of the statin benefits could not be explained by LDL-C lowering alone and is thought to be due to the pleiatropic effects of statins.*2* The NCEP ATP III guidelines” and the Malaysia Lipid CPG 2004** recommended target LDL-C of <2.6 mmol/l in CAD or CAD-risk equivalent patients. The updated ATP Ill guideline in 2004”, recommended a target of LDL-C < 1.8 mmol/| in high risk CAD patients. The 2007 update of the ACC/AHA guideline for the management of patients with SAP** recommends this level as reasonable for all patients with SAP. Recent trials*’** have shown aggressive LDL-C reduction with high-dose statin could halt plaque progression and induce plaque regression respectively. If the LDL-C target is not achieved with the maximum tolerable dose of statins, the addition of a cholesterol absorption inhibitor, ezetimide may be useful. Many statin-treated patients continue to have recurrent CV events. This residual risk could partly be explained by other dyslipidaemic parameters e.g. low-HDL-C. and high TG, especially in patients with metabolic syndrome and T2DM. Improvement in these non-LDL-C fractions and possible reduction of CAD events’? could be achieved with the addition of a fibrate or nicotinic acid. Combination therapy with fibrates may increase adverse effect. There is insufficient data to recommend a target HDL-C or triglyceride level in patients with SAP.There are benefits of ACEls in secondary prevention especially in post-Ml patients with depressed LV function (LVEF < 40%).9”*° Recent trials have investigated the use of ACEI in CAD patients without LVD. The HOPE** trial (using Ramipril 10 mg daily against placebo) and EUROPA”” trial (using Perindopril 8 mg daily against placebo) showed 20% reduction in composite primary endpoints (CV death, MI + stroke/cardiac arrest). The PEACE" trial utilising Trandolapril 4 mg against placebo did not show benefit in low risk patients (normal LVEF in whom CV risk factors are well controlled and revascularisation has been performed). However 2 large meta-analyses" have shown favourable effect of ACEIs on the outcome in CAD patients with preserved LV systolic function. Therefore, ACEI is recommended for all patients with CAD especially when there is. concomitant LV dysfunction or DM. 6.3.2.4 Angiotensin Receptor Blockers (ARBs) The effects of ARB on prognosis in IHD is less well studied and more controversial. There has been no specific ARB-intervention trial for patients with SAP. The significant incidence of ACEI-induced cough (up to 20% especially in Asian” and Black populations) has encouraged the use of ARBs in patients with CVD. In the landmark ONTARGET** trial involving 25,260 patients aged 55 years and above with CAD or DM plus additional risk factors with no evidence of CHF, telmisartan was “non-inferior” to ramipril in achieving the composite endpoints of CV death, MI, stroke, or hospitalisation for CHF. The combination of the two drugs was associated with more adverse events without an increase in benefit. In the TRANSCEND trial involving 5,926 patients with CV disease or high-risk DM without CHF who were intolerant to ACEI, telmisartan was no better than placebo in improving the primary composite end point of CV death, Ml, stroke, or admission to the hospital for CHF events. There was however benefits in the prespecified secondary outcome of CV death, Ml, and stroke. Based on current evidence, ARBs may be considered as secondary prevention therapy in CAD patients with HPT, CHF, post MI with left ventricular dysfunction (LVD) and diabetics when ACE-inhibition is indicated but not tolerated. 6.3.2.5 Heart Rate (HR) reducing agents. Beta-blockers and HR-reducing non-dihydropyridine calcium channel blockers (CCB) have been the mainstay of pharmacological treatment to achieve HR reduction. We also know that almost two-thirds of patients continue to experience an average of two angina episodes per week despite simultaneous use of multiple anti-anginal drugs.**6.3.2.5.1 Beta-Blockers Beta-blockers are the first line treatment in patients with SAP, Beta-blockers act by competitively inhibiting catecholamines from binding to 61, 2 and B3 receptors. The risk of CV death or MI was reduced by 30% with the used of beta- blockers in post-MI trials." It has been extrapolated that beta-blockers may be cardioprotective in patients with stable CAD. A meta-regression analysis*’ of effects of different beta-blockers on mortality found non significant benefits of acute treatment. However, a 24% relative risk reduction of mortality was noted with long-term secondary prevention. {1 blockade by metoprolol or bisoprolol reduces cardiac events in CHF patients while carvedilol, a non-selective beta-blocker also reduces risks of death and CV hospitalisations in CHF?" There is a lack of evidence showing benefits in this group of patients using atenolol. 6.3.2.5.2 lvabradine Several studies have shown a compelling correlation between elevated HRs and both all-cause as well as CV mortality in the general population**:** and CAD patients.*** This relationship is independent of other risk markers. HR reduction may reduce angina by reducing myocardial oxygen consumption and by increasing diastolic perfusion time. \vabradine is a first in its class of agent that acts primarily on the SA node via blockade of the ‘funny’ /¢ current. It achieves HR reduction without significant negative inotropic effect and other adverse effects associated with beta- blocker use. Common side effects include sinus bradycardia®® and reversible visual disturbances.” There is no significant interaction with various cardiac drugs e.g. AGEls, ARBs, warfarin, amiodarone, anti-platelet agents, cholesterol lowering agents, digoxin and diuretics. The INITIATIVE study*” showed that ivabradine is as effective as atenolol in improving ischaemia endpoints in patients with SAP. In the BEAUTIFUL study,” ivabradine significantly reduced ischaemic end-points of hospitalisation for fatal and non-fatal MI and the need for coronary revascularisation in patients with stable CAD, moderate LV dysfunction and HR > 70 bpm. \vabradine may be considered for symptomatic treatment of SAP in patients with normal sinus rhythm, especially in those who have a contraindication to or intolerance to beta-blockers. It may also be used in combination with beta- blockers in patients whose resting HR remains high.” 6.3.2.5.3 Non-dihydropyridine Calcium Channel Blockers (CCBs) HR-lowering CCBs - diltiazem and verapamil may be used as an alternative to beta-blockers in patients without CHF who do not tolerate beta-blockers.The APSIS trial comparing metoprolol CR against verapamil SR showed similar CV event rates in both groups of patients with SAP especially in females without DM.’ 6.3.2.6 Calcium Channel Blockers (CCBs) CBs act by blocking calcium channels in muscle cells of the heart and blood vessel, resulting in vasodilatation, increasing coronary blood flow and decreasing the myocardial oxygen demand. The non-dihydropyridine CCBs have an additional effect of reducing HR. Randomised clinical trials comparing CCB and beta-blockers have demonstrated that CCB are generally as effective as beta blockers in relieving angina and improving exercise time to onset of ischaemia or angina.” 6.3.2.6.1 Dihydropyridine Calcium Channel Blockers (CCBs) Earlier trials of short acting nifedipine showed no prognostic benefit regarding in CAD patients. In the ABCD** trial, the use of nisoldipine, a short acting dihydropyridine CCB, was associated with a higher incidence of fatal and nonfatal MI compared with enalapril. A meta-analysis of 16 trials using immediate release and short acting nifedipine in MI and UA reported a dose related influence on excess mortality.’ The use of short acting dihydropyridine CCB as monotherapy is discouraged,”*"*** Long acting dihydropyridine CCB may be safe as shown in the ACTION trial, with less coronary interventions in the CCB group but no reduction in the composite endpoints of death, MI, refractory angina, debilitating stroke CHR. 6.3.2.6.2 Non-dihydropyridine Calcium Calcium Channel Blockers (CCBs) See section 6.3.2.5.3 6.3.2.7 Nitrates Nitrates are both venous and arterial dilators. It reduces myocardial oxygen demand via its reduction of LV volume and arterial pressure via preload reduction.**:*"* The vasodilatory effect on epicardial arteries and collateral vessels improves the oxygen supply. The clinical benefits of nitrates are mainly seen in symptom improvement e.g. reduction of angina episodes, improvement in exercise tolerance and increase in time to onset of ischaemia.****” It has no prognostic benefit. Rapidly acting formulation of nitroglycerin provides effective symptoms relief of angina pectoris and maybe used for situational prophylaxis." The anti-ischaemic effect is additive when used in combination with other antianginal medications e.g. beta-blockers and CCB.7* Long-acting nitrates reduces the frequency and severity of anginal attacks and may increase exercise tolerance. These drugs failed to show prognostic benefit and areonly for symptomatic relief of angina, e.g. isosorbide-5-mononitrate. The long acting-nitrates come in tablet, transdermal patch and ointment formulations. Nitrate tolerance may develop if used continuously resulting in breakthrough angina. Hence, nitrate-free periods (8 - 12 hours) are encouraged. Rebound angina may happen during this nitrate-free interval. Nitrates should be used with caution in patients with severe hypertrophic obstructive cardiomyopathy and severe aortic stenosis. PDE5-inhibitor use is contraindicated in patients who are on nitrate therapy.’ The most common side effect is headache. 6.3.2.8 Trimetazidine Trimetazidine inhibits 3-KAT (3-ketoacyl CoA thiolase) enzyme in myocardial cells. This optimises cardiac metabolism by switching energy substrate preference from fatty acid oxidation to glucose oxidation which is a more efficient pathway for ATP production. This promotes a favourable demand versus (vs) supply balance in myocardial oxygen need. Trimetazidine has been shown to be effective in providing angina symptom relief, reduction in the need for nitrates and improving functional capacity in patients with angina. It is useful whether as monotherapy or in combination with other anti-ischaemic agents.””*”* It is also safe and effective in patients with ED. Therefore, it allows angina symptom relief and concomitant treatment with PDES-inhibitor for the Erectile Dysfunction (€D)."6.3.3 Other medical therapy 6.3.3.1 NSAIDS and COX 2 inhibitors NSAIDS and selective COX 2 inhibitors may increase the risk of CV complications. They should be used in the lowest effective dose and for the shortest possible duration. If analgesia is needed, it is recommended to use Non NSAIDS analgesics e.g. paracetamol or opiates. If NSAIDS and COX 2 are unavoidable, they should be used in combination with low dose Aspirin. 6.4 MYOCARDIAL REVASCULARISATION Revascularisation in patients with stable CAD confers prognostic benefit in the following high risk group of patients, and therefore should be considered as a first line treatment, along with optimal medical therapy." 1. Significant Left main stem (LMS) disease (> 50% stenosis). 2. Significant proximal multi-vessel disease with angina symptoms or in which large area of ischaemia has been demonstrated on functional testing. 3. Multi-vessel disease with impaired LV function with proven viable myocardium. In all other conditions, revascularisation may be offered following failure of optimal medical therapy to control symptoms." In asymptomatic patients, revascularisation may be offered in the presence of extensive inducible ischaemia or viable myocardium on functional tests.*** Revascularisation in patients with stable CAD may be accomplished by * Percutaneous Coronary Intervention (PCI) * Coronary Artery Bypass Grafting (CABG)6.4.1 Percutaneous Coronary Intervention (PCI) PCI is established as the less invasive procedure compared to CABG with lower procedure-related mortality (0.3 - 1.0%). The advance in drug-eluting stents (DES) has led to improved long-term results. Reported rate of 9-month major adverse cardiac events range between 7.1 to 10.3% in patients treated with DES, in contrast to bare metal stents rate between 13.3 to 18.9%." There has been some concerns regarding the safety of DES, in particular late stent thrombosis.” However, Sheishahbor et al. reported in a prospective PCI patient registry at Cleveland Clinic involving over 8,000 patients implanted with DES or bare metal stent (BMS), there was a significantly lower mortality in the DES group (8% vs. 17%) at an average follow-up of 4.5 years.”* This recent findings served as a reassurance on the safety of DES, though experts still advise caution on the small but real risk of late stent thrombosis.”* 6.4.2 Coronary Artery Bypass Grafting (CABG) CABG is known for its long-term established data on outcome in the above high risk groups especially in the presence of DM or concurrent valvular disease. This is particularly true when arterial grafts are used. Typically, the internal mammary graft has a patency rate of about 90% at ten years post-CABG. As for vein grafts, the patency rate ranges between 60 - 70% at 10 years. Patients who are deemed suitable for surgery must be thoroughly evaluated and informed of the risk. In uncomplicated patients with normal LV function and no other co-morbidity, the reported mortality rate is under 3%. 6.4.3 Percutaneous Coronary Intervention (PC!) vs. Coronary Artery Bypass Grafting (CABG) Meta-analysis comparing PCI with CABG demonstrated similar mortality rates in both groups. In the CABG group, there was a significantly higher proportion of patients who remained symptom-free. There was also lower requirement for repeat revascularisation.* The BARI trial showed significantly lower 5-year mortality in diabetics undergoing CABG compared to PCI. Recent Registry Data (New York State) comparing DES vs. CABG also showed a mortality difference in favour of CABG in patients with multi-vessel disease.” SYNTAX randomised 1,800 patients with documented multi-vessel CAD including LM stenosis to CABG or PCI. One year follow-up from the study demonstrated comparable outcomes in composite end points between the two strategies including the subset of patients with LMS. PCI resulted in a higher rate of repeat revascularisation (13.7% vs. 5.9%). CABG resulted in a higher rate of stroke (2.2% vs. 0.6%).** Evidence is now emerging regarding efficacy and safety of LMS. stenting, particularly with DESs. In low risk patients with ostial or body of LMS stenosis, PCI may be offered as an alternative (lb, B).”°* In LMS bifurcation, CABG should be preferred except when patients refused surgery following thorough explanation, or when the risk of surgery is unacceptable. Overall, there is still limited long-term data regarding PCI in LMS. Therefore, PCI of LMS cannot be routinely recommended. In patients with significant LMS disease who decline surgery (after a thorough consultation), PCI with complete revascularisation may be offered. PCI of LMS should only be carried out at experienced centres by experienced interventional cardiologists.In all cases of decision making in revascularisation, centre expertise in PCI and CABG procedure must be taken into account with the emphasis on collaboration between cardiologists and cardiothoracic surgeon. Prior to revascularisation procedures, patients must be thoroughly informed of the associated risk of mortality and morbidity, as well as long-term results."* It should be emphasised that optimal medical therapy should be offered to all patients regardless whether or not they undergo revascularisation. In patients who have undergone PCI, antiplatelet therapy should be maintained according to the standard guidelines.* The following table summarises the recommendations:2*': 282.2% 29.20 ri r Indication for PCI cna tr na with multi-vessel disease (non-DM) Indication for CABG ae oraeneels Angina with 3VD and: 4 Inducible ischaemia or LV function or : Involving proximal LAD Angina and multi-vessel disease (no DM) 6.4.4 Revascularisation vs. medical therapy Review of data from earlier trials suggested that whenever revascularisation was compared to optimal medical therapy, there were no significant difference in the outcome, with the exception of CABG in diabetic patients with multi-vessel disease.°**"' Two recently published trials have again reaffirmed the importance of optimal medical therapy. The COURAGE trial concluded that initial strategy of PC! in patients with proven coronary artery disease did not provide incremental clinical benefit over optimal medical therapy.*" BARI 2D trial in diabetic patients with multi-vessel disease concluded that medical therapy offered similar survival advantage comparing to revascularisation; with the only exception of CABG - showing lower incidents of non-fatal reinfarction. This data provides strong evidence on the importance of optimal medical therapy in all CAD patients - which should include antiplatelet, statin, beta-blocker and RAAS inhibitors. In a majority of patients optimal medical therapy is an excellent initial treatment strategy, particularly those with less severe disease.6.5 SPECIAL SUBGROUPS 6.5.1 Women 6.5.2 Diabetes Mellitus (DM) 6.5.3 Elderly 6.5.4 Chronic refractory angina 6.5.1 Women CVD is the main cause of death among women both worldwide and in Malaysia. In Malaysia it accounts for 25% of all female deaths in government hospitals. There are also numerous differences in the epidemiology of CAD between men and women. There is a significantly lower age-specific risk of CAD in women than men. Risk of death due to CAD in women is roughly similar to that of men 10 years younger. Despite their marked advantage in age-specific risk of CAD death, the greater likelihood of survival of women to advanced ages produces nearly equal numbers of actual deaths due to CAD in men and women. SAP is the most common presentation in women as compared to ACS and sudden death in men.’* °° However, women suffering from MI have a higher mortality and morbidity compared to men. This poorer prognosis is most likely due to severity of illness, increased age at presentation, and co-morbidity in women. In-hospital mortality was 13% for women vs. 7% for men. Cumulative mortality at 48 months was 36% for women vs. 21% for men.** 6.5.1.1 Clinical evaluation Evaluation of chest pain in women is less straightforward due to: * Gender differences in presentation and disease manifestation © SAP being the most frequent initial manifestation of CAD in women * MI or sudden death is the most frequent initial manifestation in men * Incidence of anginain women being higher than men in the post-menopausal age group * Incidence of fatal CAD being higher in men with angina than women with angina * Preponderance of male specific data in literature 6.5.1.2 Diagnosis 6.5.1.2.1 Clinical evaluation The diagnosis of angina in women is more difficult for the following reasons: * Atypical symptoms are more common in women * Correlation between symptoms and ‘significant’ luminal obstruction at coronary angiography is weaker in women * Angina may be associated with ischaemia in Syndrome X, in the absence of obstructive coronary lesion * Microvascular disease and coronary vasospasm are more common in women * Ischaemia may be shown by ECG, perfusion study or other methods in these patients 6.5.1.2.2 Stress testing * Exercise ECG testing has higher false positive rates in women (38 - 67%) than in men (7 - 44%)"* However exercise ECG testing has lower false-negative rates in women resulting in a higher negative predictive value * Only 30% of women need to be referred for further testing * Stress echo is an independent predictor of cardiac events in women with known or suspected CAD * Sensitivity of Thallium radionuclide perfusion scan may be lower in women These patients may respond to anti-ischaemic therapy without angiographic evidence of epicardial stenosis. 6.5.1.3 Treatment * Women tend to present at an older age and have a higher morbidity and mortality after Mi than men * Less vigorous treatment in women may impact on reduced survival * Women should be treated no less aggressively than men (For further information, please refer to Clinical Practice Guidelines on Prevention of Cardiovascular Disease in Women 2008)*” 6.5.2 Diabetes Mellitus (DM) Diabetes Mellitus (DM) is associated with an increased risk of CVD. CAD mortality is increased by three fold in diabetic men and two to five fold in diabetic women. #50 Prevalence of asymptomatic ischaemia is increased in patient with DM.*” Symptoms occur at an earlier age in diabetics. In symptomatic diabetic patients, risk stratification strategy should follow that of non-diabetics. Diabetics may have subclinical ventricular dysfunction which negatively impacts on exercise capacity. In patients with diabetes, the higher the blood glucose the greater the incidence of CVD."*** There is firm evidence of prognostic power of perfusion imaging in diabetic patients.°* Conventional therapies for CAD with nitrates, beta-blockers, CCBs, statins, anti- platelets and coronary revascularisation have similar indications in diabetic and non-diabetic patients.” Due to the chronic metabolic disturbances, patients have continuous progression of native atherosclerotic disease. This leads to extensive CAD with high rates of multi-vessel disease and restenosis.‘ *"’ DM management should include: * lifestyle and pharmacctherapy measures to achieve a near-normal HbA1c (|, B)* * long-term maintenance of near-normal blood glucose levels which substantially reduces complications and mortality in both DM types***?" * vigorous modification of other risk factors (e.g. physical activity, weight management, BP control, and cholesterol management) (I, B)#° * ACEI unless contraindicated (I, A)'>Even after successful invasive procedures, good management of CVD risk factors and a tight glycaemic control are essential for good long-term outcome.*” 6.5.3 Elderly After the age of 75 there is equal prevalence of CAD in men and women.” Complaints of chest discomfort, weakness and dyspnoea are common and evaluation of chest pain can be difficult. Co-morbidities that mimic SAP are common (e.g. gastroesophageal reflux disease). 6.5.3.1 Exercise stress ECG in the elderly * Exercisetesting may be problematic due to muscle weaknessand deconditioning * Less challenging exercise stress ECG protocols may be more appropriate’ * Arrhythmias are more common at higher exercise stress ECG workload*’ * Higher false negative rates due to higher prevalence of disease * Higher false positive rates due to higher prevalence of confounders including prior MI, conduction disturbances, HPT and LVH from valvular diseases However exercise testing remains important in the elderly despite these differences. graphy * Elderly patients with objective evidence of moderate to severe ischaemia at non-invasive testing should have similar access to coronary arteriography as younger patients" * Diagnostic coronary arteriography has relatively little increased risk in elective evaluation * The disease is more likely to be diffuse and severe * LMS stenosis, 3VD and impaired LV function are more prevalent * Age > 75 years is an important predictor of contrast-induced nephropathy** 6.5.3.3 Treatment Issues in medical treatment are dose modification, drug interactions, polypharmacy and compliance.*° Elderly patients have the same benefit from medical therapy, angioplasty and bypass surgery as younger patients.” Management of the elderly should be individualised taking into account co- morbidities and not based on age alone. 6.5.4 Chronic refractory angina Chronic stable refractory angina can be defined as a clinical diagnosis based on the symptoms of SAP, caused by ischaemia due to advanced CAD which is not controlled by a combination of maximal medical therapy, CABG and PCI. Most common reasons why revascularisation is not considered: * Unsuitable anatomy * One or several previous CABG and/or PCI * Lack of available graft conduits * Extra-cardiac diseases with increased perioperative morbidity and mortality * Advanced age, in combination with the above factorsTreatment requires optimisation of medical treatment including the use of different drugs in maximal tolerated doses, New treatment modalities under extensive evaluation: * Neuromodulation techniques (transcutaneous electric nerve stimulation and spinal cord stimulation) © Thoracic epidural anaesthesia * Endoscopic thoracic symphathectomy * Stellate ganglion blockade * Angiogenesis « Enhanced external counterpulsation (EECP) * Extracorporeal shockwave myocardial revascularisation (ESMR) * Transmyocardial (TMR) or percutaneous laser revascularisation * Heart transplantation * Drugs that modulate metabolism Neuromodulation techniques have a favourable analgesic effect with increased exercise time on treadmill but the clinical trials are small and long-term effects unknown. EECP has been evaluated for safety and effectiveness in two multi-centre registries and anginal symptoms improved in 75 - 80% of patients." ESMR has also been evaluated for safety and symptom relief in a few small studies with promising results.*°*" TMR shown conflicting results in various studies with a recent randomised controlled trial showing no benefit and no evidence of increased perfusion by PET in another study.** Chelation therapy (intravenous infusion of ethylenendiamine tetraacetic acid or EDTA is not recommended for the treatment of chronic angina or atherosclerotic cardiovascular disease and may be harmful because of its potential to cause hypocalcaemia.”REFERENCES Planning and Development Division, Health Facts 2008, Putrajaya, Ministry of Health Malaysia, May 2009. 2. Elveback LR, Connolly DC, Melton LJ Ill, Coronary heart disease in residents of Rochester, Minnesota Vil, Incidence, 1950 through 1982. Mayo Clin Proc. 1986;61:896-900. 3. Kannel WB, Feinleib M. Natural history of angina pectoris in the Framingham study. Prognosis and survival. Am J Cardiol. 1972;29:154-163. 4. Keys A. Wine, garlic, and CHD in seven countries. Lancet. 1980;1:145-146. 5. Lampe FC, Morris RW, Whincup PH, et al. Is the prevalence of coronary heart disease falling in British Men? Heart. 2001;86:499-505. 6. Fry J. The natural history of stable angina in a general practice. J A Coll Gen Pract. 1976;26:643-646. 7. Medalle JH, Goldbourt U. Angina pectoris in 10,000 men. Il. Psychosocial and other risk factors as evidenced by a multivariate analysis of a 5 year incidence study. Am J Med. 1976;60;910-921. 8. Yano K, Read DM, McGee DL. Ten-year incidence of coronary heart disease in the Honolulu Heart Program. Am J Epidemiol. 1984;119:653-666. 9. Margolis JR, Gillum RF, Feinleib M, et al. Community surveillance for coronary heart disease: the Framingham Cardiovascular Disease survey. Comparisons with the Framingham Heart ‘Study and the previous short-term studies. Am J Cardiol. 1976;37:61-67. 10. Reunanen A, Suhonen O, Aromaa A, et al. Incidence of the different manifestations of coronary heart disease in middle-aged Finnish men and women. Acta Med Scand. 1985;218:19-26. 11. Rose G, Hamilton PS, Keen H, et al. Myocardial ischemia, risk factors and death from coronary heart disease. Lancet. 1977;309:105-109, 12. Hagman M, Jonsson D, Wilhelmsen L. Prevalence of angina pectoris and myocardial infarction in ageneral population sample of Swedish men. Acta Med Scand. 1977;201:571-577. 13. Shaper AG, Pocock SJ, Walker M, et al. British Regional Heart Study: cardiovascular risk factors in middle-aged men in 24 towns. Br Med J (Clin Res Ed). 1981;283:179-186. 14. Bainton D, Baker IA, Sweetnam PM, et al. Prevalence of ischaemic heart disease: the Caerphilly and Speedwell surveys. Br Heart J. 1988;59:201-206. 15. Krogh V, Trevisan M, Panico S, et al. Prevalence and correlates of angina pectoris in the Italian nine communities study. Research Group ATS-RF2 of the Italian National Research Council. Epidemiology. 1991;2:26-82. 16. Ford ES, Giles WH, Groft JB. Prevalence of nonfatal coronary heart disease among American adults. Am Heart J. 2000;139:371-377. 17. Smith WG, Kenicer MB, Tunstall-Pedoe H, et al, Prevalence of coronary heart disease in Scotland: Scottish Heart Health Study. Br Heart J. 1990;64:295-208. 18. Mittelmark MB, Psaty BM, Rautaharju PM, et al. Prevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study. Am J Epidemiol. 1993,137:311-317. 19. The Task Force on the management on stable angina pectoris of the European Society of cardiology. Guidelines on the management of stable angina pectoris, Eur Heart J. 2006;27:1341-1381. 20. Braunwald E. Unstable angina. A classification. Circulation. 1989;80:410-414,21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. National Heart Association of Malaysia, Clinical Practice Guidelines of UANSTEMI, Putrajaya (Malaysia): Ministry of Health; 2002. National Heart Association of Malaysia. Clinical Practice Guidelines on Management of Acute ST Segment Elevation Myocardial Infarction (STEM), 2% ed, Putrajaya (Malaysia): Ministry of Health; 2007. Rosengren A, Wilhelmsen L, Hagman M, et al. Natural history of myocardial infarction and angina pectoris in a general population sample of middle-aged men: a 16-year follow-up of the Primary Prevention Study, Goteborg. Sweden. J Intern Med. 1998;244;495-505. Murabito JM, Evans JC, Larson MG, et al. Prognosis after the onset of coronary heart disease, An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation. 1993;88:2548-2555. Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group. Lancet, 1992;340:1421-1425, Dargie HJ, Ford |, Fox KM. Total Ischaemia Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. Eur Heart J. 1996;17:104-112, Rehngyist N, Hiemdah! P. Billing E, et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J. 1996;17:76-81 Pepine Cu, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International verapamil-Trandolapril study (INVEST): a randomized controlled trial. JAMA. 2003;290:2805-2816. Henderson RA, Pocock SJ, Clayton TC, et al. 7 year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Col! Cardiol. 2003;42:1161-1170. Diamond GA. A clinically relevant classification of chest discomfort. J Am Coll Cardiol. 1983; 1:574-575. Miettinen H, Lehto S, Salomaa \V, et al. Impact of diabetes on mortality after the first myocardial infarction, The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care. 1998;21:69-75. Melchior T, Kober L, Madsen CR, et al. Accelerating impact of diabetes mellitus on mortality in the years following an acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Eur Heart J. 1999;20:973-978. Haffner SM. Coronary heart disease in patients with diabetes, Engl J Med. 2000;342:1040- 1042. Hatfner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234. Rosengren A, Dotevall A, Eriksson H, et al. Optimal risk factors in the population: prognosis, prevalence, and secular trends; data from Goteborg population studies. Eur Heart J. 2001;22:136-144. Rosengren A, Hagman M, Wedel H, et al. Serum cholesterol and long-term prognosis in middle-aged men with myocardial infarction and angina pectoris. A 16-year follow-up of the Primary Prevention Study in Goteborg, Sweden. Eur Heart J, 1997;18:754-761.37. Pekkanen J), Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. New Engl J Med, 1990;322:1700-1707. 38. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation. 2000;102:1227-1232. 39. Held C, Hjemdah! P, Rehnavist N, et al. Cardiovascular prognosis in relation to apolipoproteins and other lipid parameters in patients with stable angina pectoris treated with verapamil or metoprolol: results from the Angina Prognosis Study in Stockholm (APSIS). Atherosclerosis. 1997;135:109-118. 40. Horne BD, Anderson JL, John JM, et al. Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardicl. 2005;45:1638-1643. 4). Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med. 2002;252:283-294. 42. Pearson AT. New tools for coronary risk assessment: what are their advantages and limitations? Circulation. 2002;105:886-892. 43. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study. Arch Intern Med. 1999;159:1785-1790, 44. Chakko S, Woska D, Martinez H, et al. Clinical, radiographic, and hemodynamic correlations in chronic congestive heart failure: conflicting results may lead to inappropriate care. Am J Med. 1991;90:353-359. 45. Weiner DA, Ryan TJ, McCabe GH, et al. Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease. J Am Coll Cardiol. 1984;3:772-779. 46. Hammermeister KE, DeRouen TA, Dodge HT. Variables predictive of survival in patients with coronary disease, Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations Circulation. 1979;59:421-430. 47. Witteman JC, Kok FJ, van Saase JL, et al. Aortic calcification as a predictor of cardiovascular 48. Hemingway H, Shipley M, Christie D, et al. Cardiothoracic ratio and relative heart volume as predictors of coronary heart disease mortality. The Whitehall study 25 year follow-up. Eur Heart J. 1998;19:859-869. 49. Kjekshus JK, Maroko PR, Sobel BE. Distribution of myocardial injury and its relation to epicardial ST-segment changes efter coronary artery occlusion in the dog. Cardiovasc Res. 1972;6:490-499. 50. Kleber AG, ST-segment elevation in the electrocardiogram: a sign of myocardial ischemia. Cardiovasc Res. 2000;45:111-118. 51. Lee TH, Boucher CA. Clinical practice. Noninvasive tests in patients with stable coronary artery disease. N Eng! J Med. 2001;344:1840-1845. 52. ESC. Working Group on Exercise Physiology, Physiopathology and Electrocardicgraphy. Guidelines for cardiac exercise testing. Eur Heart J. 1993;14:969-988. 53. Gianrossi R, Detrano R, Mulvihill D, et al, Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation. 1989;80:87-98. 54. Kwok Y, Kim ©, Grady D, et al, Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardio). 1999;83:660-666.55.Gibson SR. The diagnostic and prognostic value of exercise electrocardiography in asymptomatic subjects and stable symptomatic patients. Curr Opin Cardiol. 1991;6:586-546. 56. Ashley EA, Myers J, Froelicher V. Exercise testing in clinical medicine. Lancet, 2000,356:1592-1597, 57. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40:1531-1540. 58. Hung J, Chaitman BR, Lam J, et al. Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography and exercise thallium myocardial perfusion scintigraphy. J Am Coll Cardiol. 1984;4:8-16. 59. Cheitlin MD, Alpert JS, Armstrong WF, et al. ACC/AHA guidelines for the clinical application of echocardiography: executive summary. A report of the American College of Cardiology/ ‘American Heart Association Task Force on practice guidelines (Committee on Clinical Application of Echocardiography). Developed in collaboration with the American Society of Echocardiography. J Am Coll Cardiol. 1997;29:862-879. 60. Marwick TH. Current status of stress echocardiography for diagnosis and prognostic assessment of coronary artery disease. Coron Artery Dis. 1998;9:411-426. 61. Gibbons Ru, Chatterjee K, Daley J, et al. AGC/AHA/AGP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 1999;33:2092-2197. 62. Schinkel AF, Bax WJ, Geleijnse ML, et al. Noninvasive evaluation of ischaemic heart disease: myocardial perfusion imaging or stress echocardiography? Eur Heart J. 2003;24:789-800. 63. Cain P, Baglin T, Case C, et al. Application of tissue Doppler to interpretation of dobutamine echocardiograohy and comparison with quantitative coronary angiography. Am J Cardiol. 2001 ;87:525-531. 64. Cain P. Marwick TH, Case C, et al. Assessment of regional long-axis function during dobutamine echocardiography. Clin Sci (Lond). 2001;100:423-432. 65. Voigt JU, Exner B, Schmiedehausen K, et al. Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of inducible ischemia. Circulation. 2003;107:2120-2126. 66. Yip G, Abraham T, Belohlavek M, et al. Clinical applications of strain rate imaging. J Am Soc Echocardiogr. 2003;16:1334-1342. 67. Ritchie JL, Bateman TM, Bonow RO, et al. Guidelines for clinical use of cardiac radionuclide imaging. Report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. J Am Coll Cardio, 1995;25:521-547. 68. Underwood SR, Anagnostopoulos C, Cerqueira M, et al. Myocardial perfusion scintigraphy: the evidence. Eur J Nuc! Med Mal Imaging. 2004;31:261-291. 69. Wu JC, Yun JJ, Heller EN, et al. Limitations of dobutamine for enhancing flow heterogeneity in the presence of single coronary stenosis: implications for technetium-99m-sestamibi imaging, uJ Nucl Med. 1998;39:417-425. 70. Cerqueira MD. Diagnostic testing strategies for coronary artery disease: special issues related to gender. Am J Cardiol. 1995;75:52D-60D.71. 72. 73. 74. 75, 76. 77. 78. 79. 80. 81. 82. 84. 85. 87. 88. Hachamovitch R, Berman DS, Kiat H, et al. Effective risk stratification using exercise myscardial perfusion SPECT in women: gender-related differences in prognostic nuclear testing. J Am Coll Cardiol. 1996;28:34-44, Marwick TH, Shaw LJ, Lauer MS, et al. The noninvasive prediction of cardiac mortality in men and women with known or suspected coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group. Am J Med. 1899;106:172-178. Shaw LJ, Hachamovitch R, Redberg RF. Current evidence on diagnostic tasting in women with suspected coronaty artery disease: choosing the appropriate test. Cardio! Rev, 2000;8:65-74. Elhendy A, van Domburg AT, Bax WW, et al. Dobutamine-atropine stress myocardial perfusion ‘SPECT imaging in the diagnosis of graft stenosis after coronary artery bypass grafting. J Nuc! Cardiol. 1998;5:491-497. Lakkis NM, Mahmarian JJ, Verani MS. Exercise thallium-201 single photon emission computed tomography for evaluation of coronary artery bypass graft patency. Am J Cardiol. 1999;76:107-111. Shapira |, Heller I, Kornizky Y, et al. The value of stress thallium-201 single photon emission CT imaging as a predictor of outcome and long-term prognosis after CABG. J Med. 2001;32:271-282, Lauer MS, Lytle B, Pashkow F et al. Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronary-artery-bypass grafting. Lancet, 1998;351:615-622. Nandalur KR, Dwamena BA, Choudhri AF, et al. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease. A meta-analysis. J ‘Am Coll Cardiol. 2007;50:1343-1353. Nagel E, Magnetic resonance perfusion imaging for detection of ischemic heart disease. Heart Metab, 2008;38;19-21 Paetsch |, Jahnke C, Wahi A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion. Circulation. 2004;110:835-842. Hoffmann A, Burckhardt D. Evaluation of systolic murmurs by Doppler ultrasonography. Br Heart J. 1983;50:337-342, Attenhofer Jost CH, Turina J, Mayer K, et al. Echocardiography in the evaluation of systolic murmurs of unknown cause. Am J Med. 2000;108:614-620. . Fink JC, Schmid CH, Selker HP. A decision aid for referring patients with systolic murmurs for echocardiography. J Gen Intern Med, 1994;9:479-484. McKillop GM, Stewart DA, Burns JM, et al. Doppler echocardiography in elderly patients with ejection systolic murmurs. Postgrad Med J. 1991;67:1059-1061. Nagueh SF, Bachinski LL, Meyer D, et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001;104:128-130, |. Rakowski H, Sasson Z, Wigle ED. Echocardiographic and Doppler assessment of hypertrophic cardiomyopathy. J Am Soc Echocardiogr, 1988;1:31-47. Shaw LJ, Peterson ED, Kesler K, et al, A meta-analysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion, and ventricular function imaging. Am J Cardiol. 1996;78:1327-1337. Marchioli R, Avanzini F, Barzi F, et al. Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J. 2001;22:2085-2103.89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 400. 101. 102. 103. 404, 105. 106. 107. Echeverria HH, Biisker MS, Myerburg RJ, et al. Gongestive heart failure: echocardiographic insights. Am J Med. 1983;75:750-755. Fonseca C, Mota T, Morais H, et al. The value of the electrocardiogram and chest X-ray for confirming or refuting a suspected diagnosis of heart failure in the community. Eur J Heart Fail. 2004;6:807-812. Mottram PM, Marwick TH. Assessment of diastolic function: what the general cardiologist needs to know. Heart. 2005;91:681-695. Gill JB, Cairns JA, Roberts RS, et al. Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med. 1996;334:65-70. ‘Ambrose JA, Fuster V. Gan we predict future acute coronary events in patients with stable coronary artery cisease? JAMA, 1997;277:343-344. Prouafit WL, Kramer JR, Bott-Silverman C, et al. Survival of non-surgical patients with mild angina or myocardial infarction without angina, Br Heart J, 1986;56:213-221. Knez A, Becker A, Leber A,et al. Relation of coronary calcium scores by electron beam tomography to.obstructive disease in 2,11 symptomatic patients. Am J Cardiol. 2004;98:1150-1152. Becker CR. Noninvasive assessment of coronary atherosclerosis by multidetector-row ‘computed tomography. Expert Rev Cardiovasc Ther. 2004;2:721-727. Nasir K, Budoff MJ, Post WS, et al. Electron beam CT versus helical CT scans for assessing coronary calcification: current utility and future directions. Am Heart J. 2003;146:969-977. O'Rourke RA, Brundage BH, Froelicher VF, et al. American College of Cardiology/American Heart Association Exoert Consensus Document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. J Am Coll Cardiol, 2000;36:326-340, Daly G, Saravanan P, Fox K. Is calcium the clue? Eur Heart J. 2002;23:1562-1565. National Heart Association of Malaysia, College of Radiology, Academy of Medicine, Malaysia. Consensus statement on the utilization of cardiac CT, Putrajaya (Malaysia): Ministry of Health, 2008. Raff GL, Gallagher MJ, O'Neill WW, et al. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol, 2005;46:552-557. Leschka &, Alkadhi H, Piass A, et al. Accuracy of MSCT coronary angiography with 64-slice technology: First experience. Eur Heart J. 2005;26:1482-1487. Toussaint JF; LaMuraglia GM, Southern JF, et al. Magnetic resonance images lipid, fibrous, calcified, haemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation. 1996;94:932-938. Noto TJ dr, Johnson LW, Krone R, et al. Cardiac Catheterization 1990: A report of the Registry of the Society for Cardiac Angiography and Interventions (SCA&l). Catheter Cardiovasc Diagn. 1991;24:75-83, Califf RM, Armstrong PW, Carver JR, et al. 27" Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 5. Stratification of patients into high, medium and low risk subgroups for purposes of risk factor management. J Am Coil Cardiol. 1996;27:1007-1019. Hense WH. Risk factor scoring for coronary heart disease. BMJ. 2003;327:1238-1239. Daly CA, De Stavola B, Lopez Sendon JL, et al. on behalf of the Euro Heart Survey Investigators. Predicting prognosis in stable angina—results from the Euro heert survey of stable angine: prospective observational study. BMJ. 2008;392:262-267.108. 109. 110. 4114. 112. 413. 114. 115. 116. 117. 118. 119. 120. 121, 122. 123, 124, 125. Chaturvedi N, Sjolie A-K, Stephenson JM, et al, and the EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet. 1998;351:28-31. Braunwald E, Oomanski MJ, Fowler SE, st al; for the PEACE trial investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N EnglJ Med. 2004;351 :2058-2068. Harris PJ, Harrell FE Jr, Lee KL, et al. Survival in medically treated coronary artery disease. Circulation. 1979;60:1259-1 269. Mock MB, Ringqyist |, Fisher LD, et al. Survival of mecically treated patients in the coronary artery surgery study (CASS) registry. Circulation. 1982;66:562-568. Galiff RM, Mark OB, Harrell FE Jr, ét al. importance of clinical measures of ischemia in the prognosis of patients with documented coronary artery disease. | Am Coll Cardiol. 1988;11:20-26. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. Schlant RC, Forman S, Stamler J, et al. The natural history of coronary heart disease: prognostic factors after recovery from myocardial infarction in 2789 men. The 5-year findings of the coronary drug project. Circulation. 1982;66:401-414, Phillips AN, Shaper AG, Pocock SJ, et al. The role of risk factors in heart attacks occurring in men with pre-existing ischaemic heart disease. Br Heart J. 1988;60:404-410. Brewer HB Jr Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. Am J Cardiol, 1999;83:3F-12F. Hultgren HN, Peduzzi P. Relation of severity of symptoms to prognosis in stable angina pectoris. Am J Cardiol. 1984;54:988-993. Papamichael CM, Lekakis JP, Stamatelopoulos KS, et al. Ankle-brachial index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease. Am J Cardiol, 2000;86:615-618. Eagle KA, Rihal CS, Foster ED, et al. Long-term survival in patients with coronary artery disease: importance of peripheral vascular disease. The Coronary Artery Surgery Study (CASS) Investigators. J Am Goll Gardiol. 1934;23:1091-1095. Kannel WB, Abbott RD. A prognostic comparison of asymptomatic left ventricular hypertrophy and unrecognized myocardial inferction: the Framingham Study. Am Heart J. 1986;111:391-397. Sullivan JM, Vander Zwaag RV, el-Zeky F, et al. Left ventricular hypertrophy: effect on survival. J Am Coll Cardiol. 1993;22:508-513. Block Wd Jr, Crumpacker EL, Dry TJ, et al. Prognosis of angina pectoris; observations in 6,882 cases. J Am Med Assoc. 1952;150;259-264, Biagini E, Elhendy A, Schinkel AF, et al. Prognostic significance of left anterior hemiblock in patients with suspected coronary artery disease. J Am Coll Cardiol. 2005;46:858-863. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. V Eng! J Med. 1991;325:849-853, Dagenais GR, Rouleau JR, Christen A, et al. Survival of patients with a strongly positive exercise electrocardiogram. Circulation. 1982;65:452-456.126. 127. 128. 729. 130. 131. 132, 133. 134. 135. 136. 137. 138. 139. 140. 141. McNeer JF, Margolis JR, Lee KL, et al. The role of the exercise test in the evaluation of patients for ischaemic heart disease. Circulation. 1978;57:64-70. Mark DB, Hlatky MA, Harrell FE Jr, et al. Exercise treadmill score for predicting prognosis in coronary artery disease. Ann intern Med. 1987;106:793-800. Marwick TH, Mehta R, Arheart K, et al. Use of exercise echocardiography for prognostic evaluation of patients with known or suspected coronary artery disease. J Am Coll Cardiol. 1997;30:83-90. Geleijnse ML, Elhendy A, van Domburg RT, et al. Cardiac imaging for risk stratification with dobutamine-atropine stress testing in patients with chest pain. Echocardiography, perfusion scintigraphy, or both? Circulation. 1997;96:137-147. Olmos LI, Dakik H, Gordon R, etal. Long-term prognostic value of exercise echocardiography comparad with exercise 201TI, ECG, and clinical variables in patients evaluated for coronary artery disease. Circulation, 1998;98:2679-2686, Cheitiin MD, Alpert JS, Armstrong WF, et al. ACC/AHA guidelines for the clinical application of echocardiography: executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee on Clinical Application of Echocardiography). Developed in collaboration with the American Society of Echocardiography. J Am Coll Cardiol. 1997;29:862-879. Picano E, Molinaro S, Pasanisi E, The diagnostic accuracy of pharmacological siress echo echocardiography for the assessment of coronary artery disease: a meta-analysis. Cardiovasc Ultrasound. 2008;6:30. De Albuquerque Fonseca L, Picano E. Comparison of dipyridamole and exercise stress echocardiography for detection of coronary artery disease (a meta-analysis). Am J Cardiol. 2001;87:1193-1196. Sicari R, Nihoyannopoulos P, Evangelista A, et al. On behalf of the European Association of Echocardiography. Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur Echocardiogr. 2008;9:415-437 Sawada SG, Ryan T, Conley M, et al. Prognostic value of a normal exercise echocardiogram. ‘Am Heart J, 1990;120:49-55. Elhendy A, Shub C, McCully RB, et al. Exercise echocardiography for the prognostic stratification of patients with low pretest probability of coronary artery disease. Am J Med. 2001;111:18-23, Marwick TH, Case G, Vasey C, et al. Prediction of mortality by exercise echocardiography: a strategy for combination with the duke treadmill score. Circulation. 2001;103:2566-2571 Arruda-Olson AM, Juracan EM, Mahoney DW, et al. Prognostic value of exercise echocardiography in 5,798 patients: is there a gender difference? J Am Coll Cardiol. 2002;39:625-631. McCully RB, Roger VL, Mahoney DW, etal. Qutcomeatter abnormalexercise echocardiography for patients with good exercise capacity: prognostic importance of the extent and severity of exercise-related left ventricular dysfunction. J Am Coll Cardiol. 2002;39:1345-1352. Mazeika PK, Nadazdin A, Oakley CM. Prognostic value of dobutamine echocardiography in patients with high pretest likelihood of coronary artery disease. Am J Caraol. 1993;71:33-39, Poldermans D, Fioretti PM, Boersma E, ot sl, Dobutamine-atropine stress echocardiography and clinical data for predicting late cardiac events in patients with suspected coronary artery disease. Am J Med. 1994;97:119-125.142. 143. 144 145. 146. 147. 148. 149, 150. 151. 152. 153. 154, 155, 156. 157. Marcovitz PA, Shayna V, Horn RA, et al. Value of dobutamine stress echocardiography in determining the prognosis in patients with known or suspected coronary artery disease. Am J Cardiol, 1996;78:404-408. Steinberg EH, Madmon L, Patel GP, et al. Long-term prognostic significance of dobutamine echocardiography in patients with suspected coronary artery disease: results of a 5-year follow-up study. J Am Call Cardiol. 1997;29:969-973. Chuah SC, Pallikka PA, Roger VL, et al. Role of dobutamine stress echocardiography in predicting outcome in 860 patients with known or suspected coronary artery disease. Circulation. 1998;97:1474-1480. Krivokapich J, Child JS, Walter DO, et al, Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease. J Am Coll Caraiol. 1999;33:708-7 16. Poldermans D, Fioretti PM, Boersma E, et al. Long-term prognostic value of dobutamine- atropine stress echocardiography in 1737 patients with known or suspected coronary artery disease: a single-center experience. Circulation. 1999;99:757-762. Cortigiani L, Picano E, Vigna C, et al. EPIC (Echo Persantine International Cooperative) EDIC (Echo Dobutamine International Cooperative) Study Groups. Prognostic value of pharmacologic stress echocardiography in patients with left bundle branch biock. Am J ‘Med. 2004;110:361-369. Cortigiani L, Bigi R, Gigli G, et al. on behalf of the EPIC (Echo Persantine International Cooperative) EDIC (Echo Dobutamine International Cooperative) Study Groups. Prognostic significance of intraventricular conduction defects in patients undergoing stress echocardiography for suspected coronary artery disease. Am J Med. 2003;15:126-132. Cortigiani L, Picano E, Coletta C, et al, Echo Persantine International Cooperative (EPIC) Study Group; Echo Dobutamine International Cooperative (EDIC) Study Group. Safety, feasibility, and prognostic implications of pharmacologic stress echocardiography in 1482 patients evaluated in an ambulatory setting. Am Heart J. 2001;141:621-629. Metz LD, Beattie M, Hom R, et al. The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis. J Am Coll Cardiol. 2007;49:227-237, Zaret BL, Wackers FJ. Nuclear cardiology (1). N Engl J Med. 1993;329:775-783. Zaret BL, Wackers Fu. Nuclear cardiology (2). N Engl J Med. 1999;329:855-853. Brown KA, Prognostic value of thallium-201 myocardial perfusion imaging. A diagnostic tool comes of age. Circulation, 1991 ;83:363-381. Hachamovitch R, Berman DS, Shaw LW, et al. incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: difierential stratification for risk of cardiac death and myocardial infaretion. Circulation. 1998;97:535-543, McClellan JR, Travin Ml, Herman SD, et al, Prognostic importance of scintigraphic left ventricular cavity dilation during intravenous dipyridamole technetium-99m sestamibi myocardial tomographic imaging in predicting coronary events. Am J Cardiol. 1997;79:600-605. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests : Adenosine Stress Perfusion and Dobutamine Stress Wall Motion Imaging. Circulation. 2007;115:1769-1776. Greenwood JP, Younger JF; Ridgway JP. et al. Safety and diagnostic accuracy of stress cardiac magnetic resonance imaging vs exercise tolerance testing early after acute ST elevation myocardial infarction. Heart. 2007;93:1363-1368.158. Doesch C, Seeger A, Doering J, et al. Risk stratification by adenosine stress cardiac magnetic resonance in patients with coronary artery stenoses of intermediate angiographic severity. J Am Coll Cardiol img. 2009;2:424-433. 159. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left- ventricular systolic dysfunction in an urban population. Lancet. 1997;350:829-833. 160. Raymond |, Pedersen F, Steensgaard-Hansen F, et al. Prevalence of impaired left ventricular systolic function and heart failure in a middle aged and elderly urban population segment of Copenhagen. Heart. 2003;89:1422-1429. 161. Mosterd A, Hoes AW, de Bruyne MC, et al, Prevalence of heart failure and left ventricular dysfunction in the general population: the Rotterdam Study, Eur Heart J. 1999;20:447-455. 162. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation. 1994;90:2645-2657 163. Mock MB, Ringqvist I, Fisher LD, et al, Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation. 1982;66:562-568. 164. European Coronary Surgery Study Group. Long-term results of prospective randomised ‘study of coronary artery bypass surgery in stable angina pectoris. Lancet. 1982;2:1173-1180. 165. Mark DB, Nelson CL, Califf RM, et al. Continuing evolution of therapy for coronary artery disease, jnitial results from the era of coronary angioplasty. Circulation. 1994;89:2015-2025. 166. Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease (Review). Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003041. DOI:10.1002/14651858,CD003041.pub2. 167. Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine replacement therapy. J Am Coll Cardiol. 1997;29:1422-1431. implications for nicotine 168. Ranney L, Melvin C, Lux L, et al. Systematic review: smoking cessation intervention ‘Strategies for adults and adults in special populations. Ann Intern Med. 2006;145:845-856. 169. Eisenberg MJ, Filion KB, Yavin D, et al. Pharmacotherapies for smoking cessation: a meta- analysis of randomized controlled trials. CMAJ, 2008;179(2):135-144. 170. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, vareniciine, for smoking cessation. Arch Intern Med. 2006;166:1571-1577. 171. Reid RD, Quinlan B, Riley DL, et al. Smoking cessation: lessons learned from clinical trial evidence, Curr Opin Cardiol, 2007;22(4);280-285. 172. Academy of Medicine of Malaysia. Clinical Practice Guidelines on Treatment of Tobacco Use and Dependence, Ministry of Health; 2003. Available at http://www.acadmed.org.my/htmi/ dex.shtml (Accessed: 13th Aug 2009) oe 173, Graham |, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: Forth Joint Task Force of European and other societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14(Suppl 2):S1-S113. 174. Van Horn L, McCoin M, Kris-Etherton PM, et al. The evidence for dietary prevention and treatment of cardiovascular disease. J Am Diet Assoc. 2008;108:287-331. 175. Brunner EJ, Rees K, Ward K, et al, Dietary advice for reducing cardiovascular risk (Review). Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD002128. DO1:10.1002/14651858.CD002128.pub3.176. 17. 178. 179. 180. 181. 182. 183. 184, 185. 186. 187. 188. 189. 190. 191, Vogel JHK, Bolling SF, Costello RB, et al. Integrating complementary medicine into cardiovascular medicine: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). J Am Coll Cardiol. 2005;46:184-221, Kris-Etherton P, Daniels SR, Eckel RH, et al. Summary of the scientific conference on dietary fatty acids and cardiovascular health: conference summary from the nutrition committee of the American Heart Association. Circulation. 2001;103:1034-1039. De Lorgerl M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report ofthe Lyon Heart Study. Circulation. 1999:99:779-785. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMV. 4992;304:1015-1019, Academy of Medicine of Malaysia, Malaysian Association for the Study of Obesity, Malaysian Endocrine & Metabolic Society. Clinical Practice Guidelines on Management of Obesity, Putrajaya (Malaysia): Ministry of Health; 2004. Brown L, Rosner B, Willett WW, et al. Cholesterol-lowering effects of dietary fiber: a meta- analysis. Am J Clin Nutr. 1999;69:30-42, ‘Todd S, Woodward M, Tunstall-Pedoe H, et al. Dietary antioxidant vitamins and fiber in the etiology of cardiovascular disease and all-causes mortality: results from the Scottish Heart Health Study. Am J Epidemiol. 1999;150:1073-1080. Wolk A, Manson JE, Stampfer MJ, et al. Long-term intake of dietary fiber and decreased risk of coronary heart disease among women. JAMA. 1999;281:1998-2004. Medical Nutritional Therapy Guidelines for Hyperlipidemia and Hypertension, Malaysian Dietitians Association and Ministry of Health 2005. Di Casteinuovo A, Rotondo S, lacoviello L, et al. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002;1 05(24):2836-2844. Sobell LC, Sobell MB. Alcohol Consumption measure. [National Institute of Alcohol abuse and Alcohololism|. Bathesda; [updated 2004 August; cited 2008 December]. Available at: htto://pubs.niaaa.nih.gov/publications/Assesing%20Alcohol/measures:htm (Accessed: 13th ‘Aug 2009) Del Boca FK, Darkes J. The validity of self-reports of alcohol consumption: state of the science and challenges for research, Addiction. 2003;98 Suppl 2:1-12. Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med. 2004;116:682-692. Jolliffe J, Rees K, Taylor RRS, et al. Exercise-based rehabilitation for coronary heart disease. Cochrane Database of Systematic Reviews 2001, |ssue 1, Art. No.: CD001800. DOI: 10.1002/14651858.CD001800. Hambrecht R, Walther G, Mobius-Winkler S, et al. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease. A randomized trial, Circulation. 2004;109:1371-1378. Kris-Etherton PM, Harris WS, Appel LJ, et al, Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757,192. 193. 494. 495. 4196. 197. 198. 199, 200. 201. 202. 203. 204. 205. 208. 207. 208. Singh RB, Niaz MA, Sharma JP, et al. Randomized, double-blind, placebo-controlled trial of fish oil and mustard cil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-4. Cardiovasc Drugs Ther. 1997;11:485-491. Dietary supplementation with n-3 polyunsaturated fatty acids anc vitamin E after myocardial farction: results of the GISSI Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miacardico. Lancet. 1999;354:447-455. Von Schacky C, Angerer P, Kothny W, et al, The effect of dietary omega-3 faity acids on coronary atherosclerosis. A randomized, double-blind, placebo-corttrolied trial. Ann Intern ‘Med, 1999;130:554-562, Lehto S, Koukkunen H, Hintikka J, et al. Depression after coronary heart disease events. Scand Cardiovasc J. 2000;34(6):580-583. ‘Todaro JF, Shen BJ, Raffa SD, et al. Prevalence of anxiety disorders in men and women with established coronary heart disease. J Cardiopulm Rehabil Prev. 2007;27(2):86-91. Depression and depressive symptoms are highly prevalent among patients with coronary artery disease. Clinical summaries. Circulation. 2008;117(18):2309-2310. Blumenthal JA, Lett HS, Babyak MA, et al. NORG Investigators. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet. 2003;362:604-609. Jiang W, Blumenthal JA. Depression and Ischemic Heart Disease: Overview of the evidence and treatment implications. Current Psychiatry Reports. 2003;5:47-54 Lewin RuP, Furze G, Robinson J, et al. A randomised controlled trial of a self-management plan for patients with newly diagnosed angina. BrJ Gen Prac. 2002;52:194-201. Mittleman MA, Maclure M, Glasser DB. Evaluation of acute risk for myocardial infarction in men treaied with sildenafil citrate. Am J Cardiol. 2005;96:443-446. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citratre (viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo. Int J Clin Pract. 2003;57:597-600. Malaysian Urological Association and Malaysian Erectile Dysfunction Advisory Council & Training (MEDACT). Clinical Practice Guide on Erectile Dysfunction [cited 2000 August] Available at http://www.acadmed.org.my/view_file.cfm?fileid=211 (Accessed: 14th Aug 2009) Malaysian Medical Association. Guidelines for Medical Practitioners performing medical examinations for vocational licence (PSV and GDL). Available at http://www.pedom.org.my/ docinfo/docinfo-1/jpj (Accessed: 13th Aug 2009) er Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. (Steno-2).N’ Engi J Med, 2003;348:383-393. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin- converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Eng J Med. 2000;342:145-153, Fox KM for the The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placabo-controlled, multicentre trial (the EUROPA study) Lancet. 2003;362:782-788. Dagenals, GR, Pogue J, Fox K, et al. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368:581-588.209, 210. att. 212 213. 214. 215. 216. 217. 218. 219. 220. 221, 222. 223. 224. 225. 226. Malaysian Endocrine and Metabolic Society, Academy of Medicine of Malaysia, Persatuan Diabetes Malaysia, Clinical Practice Guidelines on Management of Type 2 Diabetes Mellitus, (4th edition), Putrajaya (Malaysia): Ministry of Health, 2009. Available at http:/Awww.moh.gov. my/MohPortal/DownloadServiet?id=36358type=2 (Accessed: 14" Aug 2009) American Diabetes Association. Standards of Medical Care in Diabetes — 2010. Diabetes Cara. 2010;33(Suppl 1):S11-S61. Fisman EZ, Motro M, Tenenbaum A, et al. Is hypoglycaemia a marker for increased long-term mortality risk in patients with coronary artery disease? An 8-year follow-up. Eur J Cardiovasc Prev Rehabil, 2004;11:135-143, Academy of Medicine of Malaysia. Clinical Practice Guidelines on Dyslipidaemia, (3° edition). Putrajaya (Malaysia): Ministry of Health, 2003. Available at http://www.acadmed. org.my/view_file.cfm7Tileid=186 (Accessed: 14" Aug 2009) Grundy SM, Cleeman JI, Merz CNB, et al. implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel Ill guidelines. Circulation. 2004;110:227-239. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC. guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372. Hackam DG, Intensive Reduction of Low-Density Lipoprotein-Cholesterol Implications of Recent Trials. Am.J Cardiovasc Drugs. 2006;6:367-371 Ray KK, Cannon CP Braunwaki E. Recent trials of lipid lowering. Int J Clin Pract. 2007;61:1145-1159, Robinson JG. LDL Reduction: How low should we go and is it safe? Current Cardiology Reports. 2008;10:481-487. LaRosa JC, Grundy SM, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J ‘Med. 2008;352:1425-1435. Harpaz D, Benderly M, Glodbourt U, et al, for the Israeli BIP Study Group. Effect of aspirin on mortality in women with symptomatic or silent myocardial ischemia. Am J Cardiol. 1996;78:1215-1219. Patrono C, Coller B, Fitz Gerald GA, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolyte Therapy. Chest. 2004;126 (suppl. 3); 2348-2645. CAPRIE Steering Gommittee. A randomized, blinded trial of clopidogrel versus aspiring In patients at risk of ischaemic events (CAPRIE). Lancet. 1998;348:1329-1339. Weil J, Golin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310:827-830. Kaufman PA, Mandinov L, Seiler C, et al. Impact of exercise-induced coronary vasomotion on anti-ischaemic therapy. Coron Artery Dis, 2000;11:363-369. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol- lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;386:1267-1278. MRG/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high- risk individuals: 2 randomised placebo-controlled trial. HPS Collaborative Group. Lancet. 2002;360:7-22. Almuti K, Rimawi R, Spevack D, et al. Effects of statins beyond lipid lowering: Potential for clinical benefits. int J of Cardiol. 2006;109:7-15.22) 8 221 22! 230. 23: 232. 233. 234. z 235. & 236. S 237. S 23) 24 241. 24 243. of 2 Ss s . Calabra P and Yeh ETH. The pleiotropic effects of statins. Gurr Opin Cardiiol. 2005;20:541-546, Liao JK. Clinical implications for statin pleiotropy. Curr Opin Lipidol. 2005;16:624-629. Grundy SM, Cleeman JI, Bairey Merz GN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel Ill Guidelines. J Am Coll Cardiol. 2004;44:720-732. Fraker TD Jr, Fin SD, writing on behalf of the 2002 Chronic Stable Angina Writing Committee. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the Management of Patients With Chronic Stable Angina. J Am Coll Cardiol. 2007;50:2264-2274. Nissen SE, Tuzcu EM, Schoenhagen P, et al; for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA, 2004;291:1071-1080. Nissen SE, Nicholls SJ, Sipahi | et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID trial. JAMA. 2006;295:1556-1565. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL-cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care, 2003;26:1513-1517. Robins SJ, Collins D, Wittes JT, et al; for the VA-HIT Study Group. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA, 2001;285:1585-1591. Harold Bays. Statin Safety: an overview and assessment of the data—2005. Am J Cardiol. 2006;97[suppl 1]:6C-26C. Pasternak RC, Smith SC, Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. J Am Coll Cardiol. 2002;40:567-572. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of hoart failure. Lancet, 1993;342:821-828. Fourth International Study of Infarot Survival Collaborative Group. A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. ISIS-4. Lancet. 1995;345:669-685. GISSI-3 Investigators. Gruppo Italiano per lo Studio della Soprawivenza nell'infarto Miocardico. Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1 115-1122. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Eng! J Med. 1991;325:293-302. ‘Al-Maliah MH, Tleyjeh IM, Abdel-Latif AA, et al. Angictensin-converting enzyme inhibitors in coronary artery disease end preserved left ventricular systolic function. a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2008;47:1576-1583. Visser LE, Stricker BH, Van Der Velden J, et al. Angiotensin converting enzyme inhibitor associated cough: a population-based case-contro) study. J Clin Epidemiol. 1995;48:851-857. Yusuf S, Teo KK, Pogue u, et al; for the ONTARGET investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Eng/ J Med. 2008;358:1547-1559.244, 245, 246. 247, 248. 249. 250. 251 252. 253, 254. 255. 256. 257. 258. 259, 260. 261, The TRANSCEND Investigators. Effects of the angiotensin-receptor blocker telmisartan ‘on cardiovascular events in high-risk patients intolerant to angictensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372:1174-1183. Pepine GJ, Abrams J, Marks RG, et al, Characteristics of a contemporary population with angina pectoris: TIDES Investigators. Am J Cardiol. 1994:74:226-231 Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. L. Treatments following myocardial infarction. JAMA. 1988;260:2088-2093. Freemantle N, Urdahi H, Estaugh J, et al. What is the place of beta-blockade in patients who have experienced a myocardial infarction with preserved left ventricular function? Evidence and (mis)interpretation. Prog Cardiovascular Dis, 2002:44:243-250. MERIT-HF Study Group Effect on metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007. CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study il (CIBIS-I): a randomized tral. Lancet. 1999;353:9-13. Packer M, Bristow MR, Cohn JN, etal. The effect of carvedilol on morbidity and mortality in Patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Eng J Med. 1996;334:1349-1355. Kennel WB, Kannel C, Paffenbarger RS Jr, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494. Aboyans V, Criqui MH. Can we improve cardiovascular risk prediction beyond risk equations in the physician's office? J Clin Epidemiol. 2006;59:547-558. Diaz A, Bourassa MG, Guertin MC, et al, Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. Fox K, Ford |, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008/372:817-821. Savelieva |, Camm A. |; inhibition with ivabradine: electrophysiological effects and safety. Drug Safety. 2008;31:95-107. Savelieva |, Camm AJ. Absence of direct effects of the /; current blocker ivabradine on ventricular repolarisation: analysis based on population heart rate correction formula [abstract no. 1023-272] J Am Coll Cardiol. 2005;45(Suppl A): 954. Tardiff.JC, Ford |, Tendera M, et al. Efficacy of ivabradine, a new selective /; inhibitor, compared with atenolol in patients with chronic stable angina, Eur Heart J. 2005;26:2529-2536 Fox K, Ford |, Steg PG, Tendera M, Robertson M, Ferrari JEAUTIFUL Committees and Investigators. MorBidity-mortality EvAIUaTion of the i inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL): Main Results. Lancet 2008;372:607-815. Tardif JP, Ponikowski P, Kahan T for the ASSOCIATE Study Investigators. Efficacy of the /f current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 200! 540-548. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. NV Eng! J Med. 1998;338:645-652. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326-1331.262. 263. 264, 265. 266. 267. 268. 269, 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet. 2000;356:1949-1954. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction association with antihypertensive drug therapies. JAMA. 1995:274:620-625. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION Trial) randomized controlled trial. Lancet. 2004;364:849-857. ‘Abrams J. Nitroglycerin and jong-acting nitrates in clinical practice. Am J Med. 1983;74:85-94. Kaski JC, Plaza LR, Meran DO, et al. Improved coronary supply: prevailing mechanism of action of nitrates in chronic stable angina. Am Heart J. 31 10:238-245. Bassan MM, Weiler-Ravell D, Shelev ©. Comparison of the antianginal effectiveness of nifedipine, verapamil, and isosorbide dinitrate in patients receiving propranolol: a double- blind study. Circulation. 1983;68:568-575, Emanuelsson H, Ake H, Kristi M, et al. Effects of diltiazem and isosorbide-5-mononitrate, alone and in combination, on patients with stable angina pectoris. Eur J Clin Pharmacol. 1989;36:561-565. Akhras F, Chambers J, Jefferies S, et al. A randomised double-blind crossover study of Isosorbide mononitrate and nifedipine retard in chronic stable angina. Int J Cardiol 1989;24:191-196. Akhras F, Jackson G. Efficacy of nifedipine and isosorbide mononitrate in combination with atenolol in stable angina. Lancet. 1991;338:1036-1039. Parker JD, Parker JO: Nitrate therapy for stable angina pectoris. N Eng/ J Med. 1998;338:520-531. Thadani U, Lipicky Ru. Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc Drugs Ther. 1994;8:611-623. Bassan MM, Weiler-Ravell D. The additive antianginal action of oral isosorbide dinitrate in Patients receiving propranolol. Magnitude and duration of effect. Chest. 1983;83:233-240. Michael Kirby. Management of erectile dysfunction in men with cardiovascular conditions. BrJ Cardiol, 2003;10:305-307. Chazov El, Lepakchin VK, Zharova EA, et al. Trimetazidine in angina combination therapy = the tact study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. American Journal of Therapeutics. 2005;12°35-42. Jackson G. Stable angina: maximal medical therapy is not the same as optimal medical therapy. Int J Clin Pract. 2000;54:351-352. Jackson G. Combination therapy in angina: a review of combined haemodynamic treatment and the role for combined haemodynamic and cardiac metabolic agents, Int J Clin Pract. 2001 ;55:256-261. Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable effort angina using trimetazidine and metoprolol. Results of a randomized, double-blind, multicentre study (TRIMPOL Il) Eur Heart J. 2001;22:2267-2274. Rosano GMC, Marazzi G, Patrizi R, et al. Comparison of trimetazidine plus sildenafil to chronic nitrates in the control of myocardial ischemia duting sexual activity in patients with coronary artery disease. Am J Cardiol. 2005;95:327-331.280. 281, 282, 283. 284, 285, 286, 287, 288. 289. 290. 291. 292, 298, 294. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Tiialists Collaboration. Lancet. 1994;344:583-570. Boden WE, O'Rourke RA, Teo KK, et al; for the COURAGE THal Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516. RITA-2 trial participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2) trial. Lancet. 1997;350:461-468, Davies RF, Goldberg AD, Forman §, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation. 1997;95:2037-2043. Morice MC, Serruys PW, Sousa JE, at al; for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization N Engl J Med. 2002;346:1773-1780. Lansky AJ, Costa RA, Mintz GS, et a; for the DELIVER Clinical Trial Investigators. Non- polymer-based paciitaxel-coated coronary stants for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation. 2004;109:1948-1954. Moses JW, Leon MB, Popma.JJ, et al; for the SIRIUS Investigators, Sirolimus-eluting stents: versus standard stents in patients with stenosis in a native coronary artary. N Engl J Med. 2003;349:1315-1323. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al; for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006;48:2584-2591. Shishehbor MH, Goel SS, Kapadia SR, et al. Long-term impact of drug-eluting stents versus bare-metal stents on all-cause mortality. J Am Coll Cardiol. 2008;52:1041-1048, Grines CL, Bonow RO, Casey DE ur, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, With Representation From the American College of Physicians. Circulation. 2007;115:813-818. Cameron A, Davis KB, Green G, et al. Coronary bypass surgery with internal-thoracic-artery grafts-effects on survival over a 15-year period. N Eng! J Med. 1996;334:216-219. Lytle BW, Blackstone EH, Loop FD, et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg. 1999;117:855-872. Smith SC Jr, Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary interventions (revision ‘of the 1993 PTCA guidelines)-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001;37:2215-2238. Bravata DM, Gienger AL, McDonald KM, et al. Systematic review: the comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft ‘surgery. Ann intern Med. 2007;147:703-716. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. NV Eng! J Med. 1996;335:217-225.295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312. Hannan EL, Wu C, Walford G, et al, Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med. 2008;358:331-341. Serruys PW, Morice M-C, Kappetein AP, et al; for the SYNTAX Investigators, Percutanzous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Eng]! J Med. 2009;360:961 -972. Chietto A, Park SJ, Valgimigli M, et al. Favorable long-term outcome after drug-eluting stent implantation in nonbifurcation lesions that involve unprotected left main coronary artery: a multicenter registry. Circulation. 2007;116:158-162. Seung KB, Park D-W, Kim Y-K, et al. Stents versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease. N Eng! J Med. 2008;358:1781-1792. Parisi AF, Folland ED, Hartigan P: A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med, 1992;326:10-16, Hueb WA, Bellotti G, de Oliveira SA, et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Cail! Cardiol. 41995;26:1600-1605. BARI Investigators. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol. 2007;49: 1600-1608. Hiatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessei disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373:1190-1197. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease, N Engl J Med. 2009;360:2503-2515. Dr Feisul idzwan Mustapha. Number of discharges and deaths in government hospitals. NCD, Information and Documentation System Unit, Putrajaya (Malaysia): Ministry of Health, 2008. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population, Am heart J. 1986;11 1:383-390. Tofler GH, Stone PH, Muller JE, et al, and the MILIS Study Group. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women. J Am Coll Cardiol. 1987;9:473-482. National Heart Association of Malaysia, Academy of Medicine of Malaysia, Clinical Practice Guidelines on Prevention of Cardiovascular Disease in Woman (1* edition). Putrajaya (Malaysia): Ministry of Health, 2008. Available at http://Awww.moh. gov.my/MohPortal/ DownloadServlet?id=2449&type=2 (Accessed: 14" Aug 2009) Sowers JR. Diabetes in the elderly and in women: cardiovascular risks. Cardio! Clin. 2004;22:541-551, McFarlane Si, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab. 2001;86:713-718. Blendea MC, McFarlane SI, lsenovic ER, et al. Heart disease in diabetic patients. Curr Diab ‘Young LH, Jose P, Chyun D. Diagnosis of GAD in patient with diabetes: who to evaluate. Curr Diab Rep, 2008;3:19-27, Fang ZY, Sharman J, Prins JB, et al. Determinants of exercise capacity in patients with type 2 diabetes. Diabetes Care. 2005;28:1643-1648,313. 314, 315. 316. 317, 318, 319, 320. 324, 322, 323. 324, 325, 326. 327, 328, 329. 330. Turner RC, Milins H, Nell HA, et al. Risk factors for coronary artery disease in non-insulin diabetes mellitus; United Kingdom Prospective Diabetes Study (UKPDS: 23). BM. 1998;316:823-828. Wel M, Gaskill SP, Hatiner SM, etal. Effects of diabetes and level of glycaemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care. 1998;21:1167-1172. Giri S, Shaw LJ, Murthy DR, et al. Impact of diabetes on the risk stratification using stress single-photon emission computed tomography myocardial perfusion imaging in pationts with symptoms suggestive of coronary artery disease. Circulation, 2002;105:32-40. Stand! E, Schnell O, A new look at the heart in diabetes mellitus: from ailing to failing Diabetologica. 2000;43:1455-1469. Way KJ, Katai N, King GL. Protein kinase G and the development of diabetic vascular complications. Diabet Med. 2001;18:945-959. The American Association of Clinical Endocrinologist Medical Guidelines for the management of diabetes mellitus. The AACE System of intensive diabetes self-management-2002 upaate. Endoor Pract Suppl. 2002:8(Supp! 1):40-82. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and tisk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. Hellman R, Regan J, Rosen H. Effect of intensive treatment of diabetes of the risk of death or renal failure in NIDDM and IDDM. Diabetes Care. 1997;20:258-264. The American Association of Clinical Endocrinologists Medical Guidelines forthe Management of Diabetes Mellitus: The AACE system of intensive diabetes self management-2000 update. Endocr Pract, 2000;6:43-84, Lernfelt B, Landahi S, Svanborg A. Coronary heart disease at 70, 75 and 79 years of age: a longitudinal study with special reference to sex differences and mortality. Age Ageing. 1990;19:297-303. Kasser|S, Bruce RA. Comparative effects of aging and coronary heart disease on submaximal and maximal exercise. Circulation. 1969;39:759-774. Vasilomanolakis EC. Geriatric cardiology: when exercise stress testing is justified. Geriatrics. 1985;40:47-50-53-4,57. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast- induced nephropathy alter percutaneous coronary intervention: development and initial validation, J Am Coll Cardiol, 2004;44;1393-1399, Montamat SC, Cusack BU, Vestal RE. Management of drug therapy in the elderly. N Eng J Med. 1989;321:303-309. Gundersen T, Abrahamsen AM, Kjekshus J, et al. Timolol-related reduction in mortality and reinfarction in patients ages 65-75 years surviving acute myocardial infarction. Prepared for the Norwegian Multicentre Study Group. Circulation. 1982;66;1179-1184. Metzger JP, Tabone X, Georges JL, et al. Coronary angioplasty in patients 75 years and older; comparison with coronary bypass surgery. Eur Heart J. 1994;15:213-217. Bonnier H, de Vries C, Michels R, et al. Initial and jong-term results of coronary angioplasty and coronary bypass surgery in patients of 75 or older. Br Heart J. 1993;70:122-125, Yang EH, Barsness GE, Gersh BJ, et al. Current and future treatment strategies for refractory angina. Mayo Clin Proc. 2004;79:1284-1292.331. 332. 333. 334. 335. 336, 337. 338. 339. 340. 341. Faircloth ME, Redwood SR, Marber MS. Strategies for refractory angina-electric not eclectic? Int J Clin Pract. 2004;58:650-652. Kim MC, KiniA, Sharma SK. Refractory angina pectoris: mechanism and therapeutic options. J Am Col! Gardial, 2002;39:923-934, AroraRR, Chou TM, Jain D, et al. The multicentre study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischaemia and angina episodes. J Am Coll Cardiol. 1999;33:1833-1840. Soran O, Kennard ED, Klesey SF, et al. Enhanced external counter-pulsation as treatment for chronic angina in patients with left ventricular dysfunction: a report from the International EECP Patient Registry (IEPR). Congest Heart Fail. 2002;8:297-302. Naber C, Ebralidze T, Lammers S, et al. Non Invasive Cardiac Angiogenesis Shockwave Therapy (NI-CATh) increases perfusion and exercise tolerance in endstage CAD patients. Submitted to WCC 2006. Fukumotao Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischaemia in patients with severe coronary artery disease. Coron Artery Dis. 2008;17:63-70. Linnemeier G, Rutter MK, Barsness G, et al. Enhanced External Counterpulsation for the relief of angina in patients with diabetes: safety, efficacy and 1-year clinical outcomes. Am Heart J. 2003;146:453-458. Leon MB, Kornowski R, Downey WE, et al. A blinded, randomized, placebo-contralled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol. 2005;46:1812-1819. Rimoldi 0, Burns SM, Rosen SD, et al. Measurement of myocardial blood flow with positron emission tomography before and after transmyocardial laser revascularization. Circulation. 4999;100(Suppl. Il):I-134-II-138. Seely DM, Wu P, Mills EJ. EDTA chelation therapy for cardiovascular disease: a systematic review. BMC Cardiovasc Disord, 2005;5:32. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. N Eng J Med. 1979;300:1350-1358,Appendix 1 Table 11. Probability of coronary disease in symptomatic patients based on (a) age, gender, and symptom classification and (6) modified by exercise test result (a) Pre-test likelihood of CAD in symptomatic patients according to age and sex Non-anginal chest pain Typical angina Re Te Oak Female 30-39 697432 258266 40-49 87341.0 55.2465 50-59 92.0206 79.4424 60-69 94.3404 90.14 1.0 Atypical angina Male 21.8424 46.1218 58.9415 67.1213 Female 42413 13.3429 32.443.0 54.422.4 Male 5.2408 141413 215417 28.1219 Female 0.8403 2.8407 84212 18.6+1.9 (b) GAD post-test likelihood (%) based on age, sex, symptom classification, exercise- induced electrocardiographic ST-segment depression Age (years) 30-39 40-49 50-59 ST-Depression (my) 0.00 - 0.04 0.05 - 0.09 0.00 -0.14 0.00 - 0.19 0.00 - 0.24 > 025 0.00 - 0.04 0.00 - 0.09 0.00 -0.14 0.00 - 0.19 0.00 - 0.24 > 025 0.00 - 0.04 0.00 - 0.09 0.00-0.14 0.00 - 0.19 0.00 - 0.24 > 025 0.00 - 0.04 0.00 - 0.09 0.00-0.14 0.00 - 0.19 0.00 -0.24 > 0.25 Typical Non-anginal angina chest pain Male Female Male Female Male Female 25 7 6 1 1 <1 68 24 24 4 5 1 83 42 38 9 10 2 91 59 55 15 19 3 96 79 76 33 39 8 99 93 92 63 68 24 61 22 16 in 4 1 86 53 44 12 13 3 94 72 64 25 26 6 97 84 78 39 a1 1 99 93 1 63 65 24 >99 98 97 86 87 53 73 47 25 10 6 2 91 78 87 31 20 8 96 8g 5 50 37 16 98 94 86 67 53 28 99 98 94 84 75 50 >99 «99 98 95 1 78 79 69 32 24 8 ii 94 90 65 52 26 7 97 95 81 72 45 33 99 98 89 83 62 49 99 99 96 93 81 72 >99 9g 99 98 94 90 Asymptomatic Male Female <1 <1 2 4 ey 7 1 18 3 a3 1 <1 5 1 "i 2 20 4 39°10 6 28 2 1 9 3 19 7 3t 12 5427 Bt 56 3 2 1 7 23 45 378 647 8 = 76Appendix 2 Recommendations for routine non-invasive investigations in evaluation of SAP Test For For diagnosis Prognosis Laboratory tests Full blood count, creatinine ic Fasting glucose iB Fasting lipid profile \.B hs-CRP, homocysteine, Ip(a), ApoA, ApoB Wo, B ECG Initial evaluation 1, During episode of angina I Routine periodic ECG on successive visits tt Ambulatory ECG monitoring ‘Suspected arrhythmia LB Suspected vasospastic angina Nia, C Suspected angina with normal exercise test lla, C CXR Suspected CHF or abnormal cardiac auscultation IB Suspected significant pulmonary disease \B Echocardiogram Suspected heart failure, abnormal auscultation, 1B 1B abnormal ECG, Q waves, BBB, marked ST-changes Previous MI 1B HPT or DM 1, B/C Intermediate or low risk patient not due to have ic lla, C alternative assessment of LV function Exercise ECG First line for initial evaluation, unless unable to ,B LB exercise/ECG not evaluable Patients with known CAD and significant deterioration IB in symptoms Routine periodic testing once angina controlled lib, C lib, C Exercise imaging technique (echo or radionuclide) Initial evaluation in patients with uninterpretable ECG Patients with non-conclusive exercise test (but adequate exercise tolerance) Angina post-revascularisation ila, B lla, To identify location of ischaemia in planning lla, B revascularisation ‘Assessment of functional severity of intermediate lla, C lesions on arteriography Pharmacological stress imaging technique Patients unable to exercise iB Patients with non-conclusive exercise test due to poor 8 exercise tolerance To evaluate myocardial viability lla, B Other indications as for exercise imaging where local lla, B lla, B facilities favour pharmacological rather than exercise stress Non-invasive CT arteriography Patients with low probability of disease and non- IIb, C conclusive or positive stress test noAppendix 3 The following free text terms or MeSH terms (in alphabetical order) were used either singly or in combination: “3-KAT inhibitor’, “adrenergic beta-antagonist”, “ambulatory electrocardiographic monitoring”, “angina pectoris review", “angina pectoris review", “angina pectoris”, “angina”, “Angiogenesis”, “angiography”, “angioplasty”, “Angiotensin Converting Enzyme inhibitors”, “Angiotensin Receptor Blocker”, “anticoagulant”, “anti-oxidants”, “anti-thrombotic agent”, “ApoA”, “ApoB”, “aspirin”, “bare metal stents”, “behaviour modification", “CABG”, “calcium channel blocker”, “cardiac magnetic resonance imaging”, “cardiac nuclear scan”, “care management”, “chest pain", “chest X-Ray”, “chronic refractory angina”, “chronic stable angina pectoris", “chronic stable angina”, “clinical evaluation”, “co-morbidity”, “coronary angiography", “coronary arteriography”, “coronary artery bypass grafting”, “coronary artery disease”, "Cyclooxygenase-1 inhibitors”, “definition of angina pectoris”, “definition”, “diabetes mellitus”, “diagnosis and assessment”, “diagnosis”, “dietary modification”, “dietary supplement”, “dipyridamole stress echo”, “dipyridamole”, “disease management", “dobutamine stress echo”, “drug eluting stents”, “drug therapy”, “Drugs that modulate metabolism”, “Duke treadmill score”, “echocardiography”, “EECP”, “elderly”, “electrocardiography”, “electron beam computed tomography”, “EBCT”, “Endoscopic thoracic symphathectomy”, “Enhanced external counterpulsation”, “erectile dysfunction”, “ESMR”, “exercise stress test”, “Extracorporeal shockwave myocardial revascularization’, “GTN”, “guidelines for the management of patients with chronic stable angina”, “health supplements”, “Heart transplantation”, “holter electrocardiographic monitoring”, “homocysteine”, “hs-CRP”, “Hydroxy Methyl! Glutaryl-CoA reductase inhibitors”, “hypertension”, ‘uy inhibitor’, “invasive procedures”, “ischaemia”, “ivabradine”, “left main stem disease”, “lifestyle modification”, “Ip(a)”, “medication therapy Management”, “multislice Computed tomography”, “multi-vessels disease”, “myocardial infarctions”, “myocardial perfusion scintigraphy”, “Neuromodulation techniques”, “nitrates”, “nitroglycerin”, “non-invasive cardiac investigation”, “omega-3 fatty acids”, “pathophysiology”, “patient care management”, “PCI”, “percutaneous coronary intervention”, “percutaneous laser revascularisation”, “pharmacological stress echocardiography’, “physician support system”, “platelet aggregation inhibitors", “prognosis”, “revascularisation”, “risk management”, “risk stratification”, “special subgroup”, “stable angina pectoris review", “stable angina pectoris review", “stable angina pectoris", “statin”, “stellate ganglion blockade”, “stress cardiac magnetic resonance imaging”, “stress echocardiography", “stress perfusion scintigraphy”, “stress test”, “thallium myocardial perfusion scan”, “thallium scintigraphy”, “thienopyridines”, “thoracic epidural anaesthesia”, “transcutaneous electric nerve stimulation and spinal cord stimulation”, “transmyocardial", “treadmill”, “treatment modalities”, “trimetazidine”, “unstable angina”, “women”ABBREVIATIONS 2vD 3-KAT 3VD ACC ACEI ACS ADP AF AHA ARB BMI BMS BP CABG CAD CCB ccs CHF CMR COx-1 CPG cv CvD CXR DES DM DTS EBCT ECG Echo ED EECP. ESC FFR GIN HOCM HPT HTA HR IHD. IvUS two-vessel disease 3-keoacyl CoA thiolase three-vessel disease American College of Cardiology angiotensin converting enzyme-inhibitor acute coronary syndrome adenosine diphosphate atrial fibrillation American Heart Association angiotensin receptor blocker body mass index bare metal stent blood pressure coronary artery bypass graft coronary artery disease calcium channel blocker Canadian Cardiovascular Society congestive heart failure cardiac magnetic resonance cyclooxygenase 1 clinical practice guidelines cardiovascular cardiovascular disease chest X-ray drug eluting stent diabetes mellitus Duke treadmill score Electron Beam Computed Tomography electrocardiography echocardiography erectile dysfunction enhanced external counterpulsation European Society of Cardiology fractional flow reserve nitroglycerin hypertrophic obstructive cardiomyopathy hypertension Health Technology Assessment heart rate ischaemic heart disease intravascular ultrasoundLBBB LMS. WwW LVD LVEF LVH MET MOH MSCT PCI PDE-5 PVD QoL RAAS. SA SAP SBP SPECT TMR Ts UA Vs WwPW left anterior descending artery left bundle branch block left main stem left ventricle left ventricular dysfunction left ventricular ejection fraction left ventricular hypertrophy metabolic equivalent myocardial infarction Ministry of Health multislice computed tomography percutaneous coronary intervention phosphodiesterase-5 inhibitor peripheral vascular disease quality of life renin-angiotensin-aldosterone system sinoatrial stable angina pectoris systolic blood pressure single-photon emission computed tomography transmyocardial revascularisation transdermal therapeutic system unstable angina versus: Wolff-Parkinson-White syndromeACRYNOMS ABCD trial ACTION trial APSIS trial BARI 2D trial BARI trial BEAUTIFUL study CASS registry COURAGE trial EUROPA trial HOPE trial HPS tral INITIATIVE study NCEP ATP III guidelines ONTARGET PEACE trial SAPAT trial SYNTAX TRANSCEND trial Appropriate Blood pressure Control in Diabetes trial A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Angina Prognos Studien | Stockholm Bypass Angioplasty Revascularization Investigation 2 Diabetes trial Bypass Angioplasty Revascularization Investigation trial MorBidity mortality EvAlUaTion of the /; inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction study Coronary Artery Surgery Study registry Clinical Outcomes Utilizing Revascularization and AGgressive drug Evaluation trial EURopean trial on reduction Of cardiac events with Perindopril in stable coronary Artery disease Heart Outcomes Prevention Evaluation trial Heart Protection Study INternational Trlal of the AnTianginal Efficacy of WVabradinE National Cholesterol Education Program Adult Treatment Panel Ill Guidelines Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial Prevention of Events with Angiotensin Converting Enzyme inhibition trial Swedish Angina Pectoris Aspirin Trial SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery Telmisartan Randomised AssessmeNt Study in ACE- iNtolerant subjects with cardiovascular DiseaseACKNOWLEDGMENT The committee of this guideline would like to express their gratitude and appreciation to the following for their contribution: * European Society of Cardiology (of which the National Heart Association of Malaysia is an affiliate member) - for allowing the Committee to adopt the European Society of Cardiology (ESC) Guidelines on the Management of Stable Angina, 2006 as a basis for these guidelines * Panel of external reviewers who reviewed the draft * Technical Advisory Committee, Clinical Practice Guidelines, Ministry of Health for their valuable input and feedback * Health Technology Assessment Section, Ministry of Health STATEMENT OF DISCLOSURE The panel members have completed disclosure forms. No member holds shares in pharmaceutical firms or acts as consultants to such firms. Details of the disclosure are available upon request from the CPG Secretariat. SOURCES OF FUNDING This CPG was made possible by an unrestricted educational grant from Servier (M) Sdn Bhd. However, the views or interests of the funding body have not influenced in an way the contents of this CPG.