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Malaysia CPG 2011

Malaysia CPG 2011

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    Cpg ua nstemi Cpg ua nstemi Document Transcript

    • June 2011 MOH/P/PAK/219.11(GU)
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011STATEMENT OF INTENTThis guideline was developed to be a guide for best clinical practicein the management of Unstable Angina/ Non ST Elevation MyocardialInfarction (UA/NSTEMI). It is based on the best available evidence at thetime of development. Adherence to this guideline does not necessarilylead to the best clinical outcome in individual patient care. Thus, everyhealth care provider is responsible for the management of his/herunique patient, based on the clinical presentation and managementoptions available locally.REVIEW OF THE GUIDELINEThis guideline was issued in 2011 and will be reviewed in 2016 or earlierif important new evidence becomes available.CPG SecretariatHealth Technology Assessment UnitMedical Development DivisionLevel 4, Block EI, Parcel EGovernment Offices Complex62590 Putrajaya, MalaysiaAvailable on the following websites:http://www.malaysianheart.orghttp://www.moh.gov.myhttp://www.acadmed.org.my 1
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011SUMMARY1. Acute coronary syndrome is a spectrum of UA/NSTEMI and STEMI. The clinical presentation will depend on the acuteness and severity of coronary occlusion.2. The diagnosis of UA/NSTEMI is based on history ± dynamic ECG changes (without persistent ST elevation), ± raised cardiac biomarkers.3. In UA cardiac biomarkers are normal while in NSTEMI it is elevated.4. Risk stratification is important for prognosis and to guide management (Flowchart 1, pg 3).5. Initial management of intermediate/high risk patients includes optimal medical therapy with aspirin I,A and clopidogrel I,A (or ticagelor I,B), UFH I,A or LMWH I,A or fondaprinux I,A. Prasugrel may be considered as an alternative to clopidogrel in high risk patients after coronary angiography if PCI is planned I,B. (Table 1, pg 4)6. Patients with refractory angina and/or hemodynamically unstable should be considered for urgent coronary angiography and revascularization I,C.7. Intermediate/high risk patients should be considered for early invasive strategy (<72 hours). If admitted to a non-PCI centre, they should be considered for transfer to a PCI centre I,A.8. Low risk patients should be assessed non-invasively for ischemia I,A. (Fig 1, pg 5)9. All patients should receive optimal medical therapy at discharge. This includes aspirin I,A, clopidogrel I,B (or ticagrelor I,B or prasugrel I,B if given during PCI), ß-blockers I,B, ACE-I I,A or ARB (if ACE-I intolerant I,B ) and statins I,A. If recurrent or residual ischemia is present, then anti anginal therapy should also be given I,C. These include nitrates I,C , calcium channel blockers IIa, C and/or metabolic agents IIa, C (Table 1, pg 4)10. These drugs should be uptitrated as outpatient to the recommended tolerated doses I,C.11. Cardiac rehabilitation and secondary prevention programs which includes lifestyle modification is an integral component of management I,A. 2
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Flowchart 1: Risk Stratification of UA/NSTEMI Flowchart 1: Risk Stratification of UA/NSTEMI Low risk Intermediate/High Risk no angina in the past Patients with recurrent chest pain no ongoing angina Early post infarction unstable angina no prior use of Dynamic ST-segment changes antianginal therapy Elevated cardiac biomarkers normal ECG Diabetes normal cardiac Hemodynamic instability biomarkers Depressed LV function (LVEF <40%) normal LV function Major arrhythmias (VF, VT) younger age group This includes (see Table 1, pg:4): Aspirin Clopidogrel or ticagrelor (or prasugrel after coronary angiography) Antithrombotics (UFH or LMWH or Fondaparinux) β-blockers Statins ACE-I/ARB Nitrates + CCB (if β-blockers contraindicated and/or unresponsive to above) + GP IIb/IIIa inhibitor  Medical therapy* Coronary Angiography and Revascularization* * This includes aspirin + β- blockers + GTN *If patient is admitted to a non-PCI centre and has ongoing ischaemia despite optimal medical therapy, it is  Risk stratify as recommended to transfer the patient for coronary outpatient (Fig1, pg 5) angiography with view to revascularization.CCB : Calcium channel blockersUFH : Unfractionated heparinLMWH : Low Molecular Weight HeparinGP : GlycoproteinVF: Ventricular fibrillationVT: Ventricular tachycardia 3 3
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Table 1: Medications in Intermediate / High Risk Patients with UA/NSTEMITable 1: Medications in Intermediate / High Risk Patients with UA/NSTEMI Drug Initial and In- Medication Comments hospital at discharge medicationAspirin I,A I,A Continued long term if tolerating+ Clopidogrel I,A I,A Used in addition to aspirin as part of dual antiplatelet therapy. I,B To be continued at least 1 month and ideally for at least a year post UA/NSTEMI and, I,C 6-12months or longer post DES implantationor, Ticlopidine IIa,B IIa,B Used in addition to aspirin as part of dual antiplatelet therapy. This is a less preferred alternative to clopidogrel.or, prasugrel I,B I,B Used in addition to aspirin as part of dual antiplatelet therapy. Alternative to clopidogrel in high risk patients undergoing PCI.or, ticagrelor I,B I,B Used in addition to aspirin as part of dual antiplatelet therapy. Alternative to clopidogrel.+ UFH I,A - Given for 2-8 daysor, LMWH I,A - Given for 2-8 days I,A - Used in patients treated conservatively.or, fondaprinux Given for 8 days or duration of hospitalizationor, Bivalirudin I,A Used as an alternative to UFH and GPIIb/IIIa inhibitors during PCI + β-blockers 1,B I,B Should be administered early if no contraindications and continued indefinitely if ischemia is present. I,A Continued indefinitely in the presence of LV dysfunction (LVEF<40%)+ ACE-I I,A I,A Should be administered early in patients with LV dysfunction (LVEF< 40%), heart failure, diabetes, hypertension or CKD. IIa, A Should be considered long term to prevent recurrent ischemia I,B I,B As an alternative to ACE-I in intolerantor ARB patients+ Statins I, A I,A High potency statins should be used early till target LDL-C levels are achieved and continued indefinitely.+/- calcium 1,B I,B If intolerant to β-blockerschannel blockers IIa,C IIa,C Indicated for residual/ recurrent ischemia.+/- nitrates I,C I,C Indicated for residual/ recurrent ischemia. 4 4
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Figure 1: Non-invasive investigation of Low Risk Patients with UA/NSTEMI* Figure 1: Non-invasive investigation of Low Risk Patients with UA/ NSTEMI* Low Risk patients with UA/NSTEMI Normal ECG, Abnormal ECG, Good Exercise Tolerance Limited exercise tolerance Exercise/Dobutamine Stress Exercise stress test Equivocal Echocardiogram or Radionuclear Perfusion Scan Negative test Positive Equivocal / Positive Test Risk Factor Reduction + Medical Therapy for Coronary Angiogram CAD* Low risk patients have : no angina in the past no ongoing angina no prior use of antianginal therapy normal ECG normal cardiac biomarkers younger age group normal LV functionPatients who have undergone revascularization and with residual/recurrent or achange in symptoms should be investigated as above.All Intermediate/High Risk UA/NSTEMI patients should be considered for coronaryangiography and revascularization. (Flowchart 1, pg 3) 5 5
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011MESSAGE FROM THE DIRECTOR GENERAL OF HEALTHIn the last 8 years since the last CPG UA/NSTEMI was published, themanagement of this most important of prodrome to a full blown STEMI haschanged significantly. However, like in 2002, despite the World Health Statistics(2010) reporting a healthy rise in the number of doctors per population, HealthFacts 2008 from the Ministry of Health Malaysia still state that the main causeof death in the country is cardiovascular disease.It is now recognized that early, aggressive management of UA/NSTEMI canimprove clinical outcomes both in the short- and long-term. Mounting evidencein the early use of antithrombotic agents, early access to revascularization,and secondary prevention strategies, contribute to the significant reduction ofcardiovascular mortality and morbidity.In the last few years, the establishment of the National Cardiovascular Database,comprising of the Acute Coronary Syndrome (NCVD-ACS), PercutaneousCoronary Intervention (NCVD-PCI), as well as the Malaysian Cardiac SurgeryRegistry (MyCARE), has now provided us a unified tool to capture importantdata on cardiovascular disease presentation and management in our country.We now know that the incidence of ACS in Malaysia is approximately 141 per100,000 population per year, and the inpatient mortality rate is approximately7%, comparable to many developed countries. We have recorded over 8000PCI performed in Malaysia over the last 3 years, with a very low rate of seriouscomplications, particularly in elective procedures (<1%).Further, in the last few years, increasing numbers of Cardiology Units, as well aswell-run General Medicine Units, are participating in Phase I to III clinical trials.More Malaysians are now being offered the opportunity to be directly involvedin new therapies and are also being provided stringent world-class care in thecontext of a clinical trial setting.In this rapidly evolving landscape of UA/STEMI management, and a definiteincrease in patient load in the face of the rising prevalence of cardiovascular riskfactors published in the recent National Health and Morbidity Survey III, it is timenow to update this CPG UA/NSTEMI. We believe this will provide healthcareproviders with strategies, derived from contemporary evidence, to improve thediagnosis and treatment of this unpredictable condition.Dato Hasan Abdul Rahman,Director General of Health,Ministry of Health, Malaysia 6
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011FOREWARD FROM THE AMERICAN COLEGE OF CARDIOLOGYOn behalf of the American College of Cardiology I want to offer my heartycongratulations to the National Heart Association of Malaysia in their creationof this ACS NSTEMI clinical practice guideline update. Adherence to evidencebased medicine has conclusively been shown to improve clinical outcomes.The field of cardiology in particular has been relatively blessed with a plethoraof many superb international randomized clinical trials (RCT) that form thebackbone of our cardiovascular clinical practice guidelines. The translationand application of the RCT-generated evidence base to the Malaysian“bedside” is the mission of clinical practice guidelines. In particular, NHAM’sClass 1 recommendations for the management of ACS/NSTEMIs representthe “must do’s” in the management of acute coronary syndromes as these caremeasures directly lead to decrease in mortality and morbidity in cardiovasculardisease. In the United States over the past few decades a marked decreasein the cardiovascular mortality and morbidity has been achieved. Thisadmirable accomplishment is directly due to increased adherence in clinicalpractice guidelines for secondary and primary prevention of coronary diseasealong with application of evidence based strategies in the management ofacute coronary syndromes. NHAM’s clinical practice guideline reflects wellthe local care environment here in Malaysia creating the potential of savingthousands of lives though your promotion of evidence based ACS care. Theparticipation in a national acute coronary syndrome registry is an importantcomponent of the cardiovascular quality cycle. If we don’t measure it, we can’tmanage it!! We applaud the leadership of the National Heart Association ofMalaysia with its enthusiasm and expertise manifested in NHAM’s updatedACS clinical practice guidelines along with your vigorous promotion of theNCVD Malaysian Acute Coronary Syndrome Registry. The ACC looks forwardin future cardiovascular collaborations with the National Heart Associationof Malaysia in the areas of cardiovascular science, education and in thepromotion of cardiovascular quality.Congratulations and a personal toast to Malaysian heart health!Ralph Brindis, MD, MPH, FACC, FSCAIImmediate Past President,American College of Cardiology 7
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Members of the Expert Panel Members of the Expert Panel Members of the Expert Panelerson: Chairperson:amalar Rajadurai Rajadurai Dr. Jeyamalar Consultant Cardiologist, Consultant Cardiologist, Sime DarbySime Darby Medical Center Medical Center Subang Jaya, Selangor Selangor Subang Jaya, Membersers (in alphabetical order) Members (in alphabetical order) (in alphabetical order)mad Nizar Dr. Ahmad Nizar Consultant Cardiologist, Consultant Cardiologist, Sime DarbySime Darby Medical Center Medical Center Subang Jaya,Selangor Subang Jaya,Selangoruar Rapaee Dr. Anuar Rapaee Consultant Cardiologist, Consultant Cardiologist, Hospital Serdang Serdang Hospital Chandran Chandran Dr. Aris Consultant Physician, Physician, Consultant Hospital Sultanah Bainun, Ipoh Hospital Sultanah Bainun, Ipohar IsmailOmar Ismail Dr. Consultant Cardiologist, Consultant Cardiologist, Hospital Besar Pulau Pinang Hospital Besar Pulau Pinangh Maskon Dr. Oteh Maskon Consultant CardiologistCardiologist Consultant Hospital UKM, KualaUKM, Kuala Lumpur Hospital Lumpure Raman Dr. Sree Raman Consultant Physician, Physician, Consultant Hospital Tuanku Jaafar, Seremban Seremb Hospital Tuanku Jaafar, (HTA trained) (HTA trained) Kui Dr. Sim Kui Hian Hian Consultant Cardiologist, Consultant Cardiologist, Sarawak General Hospital,Kuching Sarawak General Hospital,Kuchin Azman Dr. Wan Azman Consultant Cardiologist, Consultant Cardiologist, University Malaya Medical Center University Malaya Medical Centebayaah Zambahari Zambahari Dr. Robayaah Consultant Cardiologist, Consultant Cardiologist, Institute Jantung Negara, Institute Jantung Negara, Kuala Lumpur Kuala Lumpur 8
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 External Reviewers (in alphabetical order): External Reviewers (in alphabetical order): order): External Reviewers (in alphabeticalDr. Chan Hiang Chuan Dr. Chan Hiang Chuan Consultant Physician Physician Consultant Sarawak General Hospital,Kuching Sarawak General Hospital,KuDr. Jeyaindran Sinnadurai Dr. Jeyaindran Sinnadurai Consultant Physician Physician Consultant Head of Internal of Internal Medicine, Head Medicine, Ministry Of Health, Of Health, Ministry Hospital Kuala Lumpur Lumpur Hospital KualaDr. Lee Chuey Yan Dr. Lee Chuey Yan Consultant Cardiologist Consultant Cardiologist Hospital Sultanah Aminah Johor Hospital Sultanah Aminah JohDr. Lee Fatt Soon Fatt Soon Dr. Lee Consultant Geriatrician Consultant Geriatrician Hospital Kuala Lumpur, KL Hospital Kuala Lumpur, KLDr. Kim Tan Kim Tan Dr. Consultant Cardiologist, Consultant Cardiologist, Sunway Medical Center, Center, Sunway Medical Sunway,Selangor Sunway,SelangorDr. V Paranthaman Dr. V Paranthaman Family Medicine Specialist,Specialist, Family Medicine Klinik Kesihatan Kesihatan Jelapang, Klinik Jelapang, Ipoh, PerakIpoh, PerakDr. Santha Kumari Kumari Dr. Santha Consultant Physician Physician Consultant Hospital Sultanah Rahimah Kelang K Hospital Sultanah RahimahDr. Tee Lian Kim Lian Kim Dr. Tee General Practitioner, General Practitioner, Klinik Young, Newton and Partners Par Klinik Young, Newton and Kuala Lumpur/Petaling Jaya Kuala Lumpur/Petaling JayaDr. Wong Kai Wong Kai Fatt Dr. Fatt General Practitioner, General Practitioner, LW Medical Associates LW Medical Associates Kuala Lumpur Lumpur KualaDr. Zurkarnai Yusof Dr. Zurkarnai Yusof Consultant Cardiologist Consultant Cardiologist Hospital Universiti Sains Malaysia Malay Hospital Universiti Sains Kota Baru,Kota Baru, Kelantan Kelantan 9
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011RATIONALE AND PROCESS OF GUIDELINE DEVELOPMENTRationale:Coronary artery disease (CAD) is an important cause of morbidity andmortality in Malaysia. Patients with CAD may present as stable angina oras acute coronary syndromes (ACS). ACS is a spectrum of diseaseranging from unstable angina (UA), non ST elevation myocardial infarction(NSTEMI) to ST elevation myocardial infarction depending on theacuteness and severity of the coronary occlusion. The last CPG onUA/NSTEMI was published in 2002. Thus the need for an update.Objectives:The objectives of this guideline are to: provide guidance on the most effective evidence based therapeutic strategies in patients with UA/NSTEMI to reduce in-hospital morbidity and mortality. reduce the risk of recurrent cardiac events in these patientsThis Clinical Practice Guideline (CPG) has been drawn up by a committeeappointed by the National Heart Association of Malaysia, Ministry ofHealth and the Academy of Medicine. It comprises cardiologists andgeneral physicians from the government and private sectors as well asfrom the Universities.Process:Evidence was obtained by systematic review of current medical literatureon UA/NSTEMI using the usual search engines – PubMed, Medscape andOvid. The other international guidelines (American and European) on thesubject were also studied. After much discussion, the draft was thendrawn up by the members of the Expert Panel and submitted to theTechnical Advisory Committee for Clinical Practice Guidelines, Ministry ofHealth Malaysia and key health personnel in the major hospitals of theMinistry Of Health and the Private Sector for review and feedback.The clinical questions were divided into major subgroups and members ofthe Expert Panel were assigned individual topics. The group members metseveral times throughout the development of the guideline. All retrievedliterature were appraised by individual members and subsequentlypresented for discussion during group meetings. All statements andrecommendations formulated were agreed collectively by members of theExpert Panel. Where the evidence was insufficient the recommendationswere derived by consensus of the Panel. The draft was then sent to localexternal reviewers for comments. It was also sent to the American Collegeof Cardiology and the European Society of Cardiology for feedback. 10 10
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011The level of recommendation and the grading of evidence used in thisguideline was adapted from the American Heart Association and theEuropean Society of Cardiology (ACC/ESC) and outlined on page 13. Inthe text, this is written in black on the left hand margin. In the Summaryand Key Recommendations, it is written as a superscript immediately afterthe therapeutic agent or at the end of the statement as applicable.Clinical Questions Addressed: What is the current evidence on the best practice strategies to reduce morbidity and mortality in patients with UA/NSTEMI? Which of these strategies are applicable to our local setting considering our limited health resources?Target Group:This guideline is directed at healthcare providers including generalpractitioners, medical officers, general and family physicians andcardiologists.Target Population:All patients (older than 18 years) presenting with chest pain.Period of Validity of the Guidelines:This guideline needs to be revised at least every 5 years to keep abreastwith recent developments and knowledge.Applicability of the Guidelines:This guideline was developed taking into account our local healthresources. The following are available at all state and district governmenthospitals with physicians. ECG machines, measurement of cardiac biomarkers (including troponins), treadmill stress ECG’s and echocardiograms. Most of the medications that are recommended in this guideline are already approved for use in Malaysia. Intermediate/high risk patients should be identified early and transferred to hospitals with existing catheterization facilities. In accordance with the national health plan, the ministry has already proposed the setting up of catheterization laboratories in most of the state hospitals.This guideline aims to streamline management of cardiac patients andeducate health care professional on strategies to optimize existingresources. We do not anticipate barriers to its implementation. 11 11
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Implementation of the Guidelines:The implementation of the recommendations of a CPG is part of goodclinical governance. To ensure successful implementation of this CPG wesuggest: increasing public awareness of CAD and its therapies. continuing medical education and training of healthcare providers. clinical audit – This is done by monitoring : o In-hospital mortality and morbidity in patients admitted with ACS (NCVD registry) o Readmission rates for a cardiac related event in patients discharged with a diagnosis of ACS. Elective admissions for cardiac procedure are excluded. o Documentation of the following; - Risk stratification - Discharge medications to include, antiplatelets, statins, ACE-inhibitors and Beta blockers. - Discharge plan with regards to cardiac assessment/tertiary care referral. 12 12
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011GRADES OF RECOMMENDATIONS AND LEVELS OF EVIDENCEGRADES OF RECOMMENDATION Conditions for which there is evidence and/or general agreement I that a given procedure/therapy is beneficial, useful and/or effective. Conditions for which there is conflicting evidence and/or II divergence of opinion about the usefulness/efficacy of a procedure/therapy. II-a Weight of evidence/opinion is in favor of its usefulness/efficacy. II-b Usefulness/efficacy is less well established by evidence/opinion Conditions for which there is evidence and/or general agreement III that a procedure/therapy is not useful /effective and in some cases may be harmful.LEVELS OF EVIDENCE Data derived from multiple randomized clinical trials or meta A analyses Data derived from a single randomized clinical trial or large non B randomized studies Only consensus of opinions of experts, case studies or standard C of care Adapted from the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) 13 13
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011TABLE OF CONTENTSStatement of Intent 1Summary 2Flowchart 1, Table 1, Figure 1 3-5Message from Director General of Health, MOH 6Foreward from President of American College of Cardiology 7Members of the Expert Panel 8External Reviewers 9Rationale and Process of Guideline Development 10-13 1. Introduction 15 2. Definition of terms 15-16 3. Pathogenesis 16 4. Diagnosis 17-19 4.1 History 17 4.2 Physical Examination 17 4.3 Electrocardiography 18 4.4 Cardiac Biomarkers 18-19 4.5 Other Diagnostic Modalities 19 5. Risk Stratification 20-21 5.1 Assessment of Risk 20 5.2 Rationale for Risk Assessment 20 5.3 Risk Scores for Prognosis of UA/NSTEMI 20 5.4 Risk Assessment for Bleeding 21 6. Triage 21-22 7. Management of UA/NSTEMI 22-31 7.1 Pre hospital Management 23 7.2 In Hospital Management 23-31 7.2.1 Initial Management 23 7.2.2 Antiplatelet Agents 23-25 7.2.3 Anticoagulant Therapy 25-27 7.2.4 Anti Ischemic Drug Therapy 28-30 8. Revascularization strategies 31-32 8.1 Routine early invasive management 31 8.2 Routine early conservative management 32 9. UA/NSTEMI in special groups 32-36 9.1 UA/NSTEMI in Elderly 32-34 9.2 UA/NSTEMI in Women 34 9.3 UA/NSTEMI in Chronic Kidney Disease 35 9.4 UA/NSTEMI in diabetes 36 10. Post Hospital Discharge 36-40 10.1 Medications post discharge 36-39 10.2 Investigations during Follow Up 39-40 11. Cardiac Rehabilitation 40-41 12. References 42-50 13. Appendix 51-57 14. Acknowledgement 58 15. Disclosure Statements 58 16. Source of Funding 58 14
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 20111. INTRODUCTIONCardiovascular Disease (CVD) is one of the main causes of mortality andmorbidity in Malaysia. The estimated incidence of Acute CoronarySyndrome (ACS) is 141 per 100,000 population per year, and the in-patient mortality rate is approximately 7%. This data is derived from theNational Cardiovascular Disease Database (NCVD) based on the ACS2006 Annual report1. These figures are similar to that of many developedcountries. Unstable Angina/Non ST Elevation Myocardial Infarction(UA/NSTEMI) which falls within the spectrum of ACS, is an importantcause of cardiac morbidity and mortality.The last CPG on UA/NSTEMI was published in 2002. Since then, therehave been significant advances in the management of this importantcondition. Thus, it is timely to update this CPG to keep abreast withcontemporary evidenced based state of the art management of thiscondition.2. DEFINITION OF TERMSACS is a clinical spectrum of ischemic heart disease. Depending upon thedegree and acuteness of coronary occlusion, it can present as (Figure 2,pg 16): Unstable angina (UA) Non-ST elevation myocardial infarction (NSTEMI) ST elevation myocardial infarction (STEMI)These changes may be dynamic. A patient presenting with UA mayprogress to NSTEMI or even STEMI.The terms Q-wave myocardial infarction (QwMI) and non-Q wavemyocardial infarction (NQMI) are no longer preferred.Unstable angina may be classified as2 (Appendix I, pg 51):I. New onset of severe angina or accelerated angina; no rest painII. Angina at rest within past month but not within preceding 48 hours (angina at rest, subacute)III. Angina at rest within 48 hours (angina at rest, acute)It may be further classified according to clinical circumstances into either:A) Secondary – develops in the presence of extracardiac diseaseB) Primary – develops in the absence of extracardiac diseaseC) Post-infarct – develops within 2 weeks of an acute MI 15 15
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011The diagnosis of NSTEMI is established if a cardiac biomarker is detected. The diagnosis of NSTEMI is established if a cardiac biomarker is detected. The diagnosis of NSTEMI is established if a cardiac biomarker is detected.In NSTEMI, ST/TST/T changes may present in the the ECG, whereas UA UA In NSTEMI, changes may be be present in ECG, whereas in in In NSTEMI, ST/T changes may be present in the ECG, whereas in UAthey theyusually absent and and even if they present, are are usually transient. are are usually absent even if they are are present, usually transient. they are usually absent and even if they are present, are usually transient. FIGURE 2: Pathogenesis of ACS FIGURE 2: Pathogenesis of ACS FIGURE 2: Pathogenesis of ACS Adapted with modification from Antman EM, Anbe DT, Armstrong PW et al. “ACC/AHA Guidelines Adapted with modification from Antman EM, Anbe AnbeArmstrong PW et al.et al. “ACC/AHA Guidelines Adapted with modification from Antman EM, DT, DT, Armstrong PW “ACC/AHA Guidelines for the management of patients with ST Elevation Myocardial Infarction” at www.acc.org for thefor the management of patientsST Elevation Myocardial Infarction” at www.acc.org management of patients with with ST Elevation Myocardial Infarction” at www.acc.org 3. PATHOGENESIS3. PATHOGENESIS 3. PATHOGENESIS ACS occurs due to atherosclerotic plaque rupture, fissure or ulcerationACS ACS occurs dueatherosclerotic plaque rupture, fissure or ulceration occurs due to to atherosclerotic plaque rupture, fissure or ulceration with superimposed thrombosis and coronary vasospasm. Depending onwith with superimposed thrombosis and coronary vasospasm. Depending on superimposed thrombosis and coronary vasospasm. Depending on the acuteness, degree of occlusion and the presence of collaterals,the acuteness, degree of occlusion and and the presence collaterals, the acuteness, degree of occlusion the presence of of collaterals, patients can present as UA, NSTEMI or STEMI.patients can present as UA, UA, NSTEMI or STEMI. patients can present as NSTEMI or STEMI. The aetiology of the plaque fissure or rupture is still unclear. PossibleThe The aetiologythe plaque fissure or rupture is still still unclear. Possible aetiology of of the plaque fissure or rupture is unclear. Possible causes include inflammation, infection, uncontrolled blood pressure andcauses include inflammation, infection, uncontrolled blood pressure andand causes include inflammation, infection, uncontrolled blood pressure smoking. ACS occurring de novo is called Primary UA/NSTEMI. smoking. occurring de novo is called Primary UA/NSTEMI.smoking. ACSACS occurring de novo is called Primary UA/NSTEMI. Occasionally UA/NSTEMI is secondary to a precipitating condition, whichOccasionally UA/NSTEMI is secondary to ato a precipitating condition, which Occasionally UA/NSTEMI is secondary precipitating condition, which is extrinsic to the coronary arterial bed. This is called secondaryis extrinsic to the the coronary arterial bed. This called secondary is extrinsic to coronary arterial bed. This is is called secondary UA/NSTEMI and can occur due to:UA/NSTEMI and can occur due due to: UA/NSTEMI and can occur to: increased myocardial oxygen demand as occurring in fever, increased myocardial oxygen demand as as occurring in fever, increased myocardial oxygen demand occurring in fever, tachycardia and thyrotoxicosis tachycardia and and thyrotoxicosis to hypotension tachycardia thyrotoxicosis reduced coronary blood flow due reduced coronary blood flow due to hypotension reduced coronary blood flow due to hypotension reduced myocardial oxygen delivery in anaemia or hypoxemia reduced myocardial oxygen delivery in anaemia or or hypoxemia reduced myocardial oxygen delivery in anaemiahypoxemia Secondary UA/NSTEMI is an important cause of ACS in the elderly.Secondary UA/NSTEMI is an important cause of ACS in the the elderly. Secondary UA/NSTEMI is an important cause of ACS in elderly. 16 16 16 16
    • Clinical Practice Guidelines on management of Unstable Angina/Non STElevation Myocardial Infarction (UA/NSTEMI) 20114. DIAGNOSIS4.1 HistoryThe symptoms of UA/NSTEMI may be indistinguishable from that ofSTEMI. These include: Chest pain - This is the presenting symptom in most patients. Chest pain or discomfort is usually retrosternal, central or in the left chest and may radiate to the jaw or down the upper limb. It may be crushing, pressing or burning in nature. The severity of the pain is variable.A significant number of patients, especially women, diabetics andthe elderly, present with atypical symptoms3. These include : Dyspnoea without any history of chest pains. Unexplained sweating, nausea and vomiting, syncope and presyncope, fatigue and epigastric discomfort. In patients with these presentation(s) and with a prior history of coronary artery disease (CAD), a family history of premature CVD, diabetes and other cardiovascular risk factors, the index of suspicion of ACS should be high. Prior history of diabetes and renal disease will influence management4,5.4.2 Physical ExaminationThe objective of the physical examination is to identify: possible causes, precipitating causes and consequences of UA/NSTEMIUncontrolled hypertension, anaemia, thyrotoxicosis, severe aorticstenosis, hypertrophic cardiomyopathy and other co-morbidconditions such as lung disease should be identified.Presence of left ventricular failure (hypotension, respiratorycrackles or S3 gallop) and arrhythmias carry a poor prognosis.Carotid bruits or peripheral vascular disease indicates extensiveatherosclerosis and a higher likelihood of concomitant CAD. 17 17
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 4.3 Electrocardiography The ECG adds support to the diagnosis and provides prognostic information6-11. A recording made during an episode of chest pain is particularly valuable.I, C It should be performed within 10 minutes of the patient’s arrival at the Emergency Department. Features suggestive of UA/NSTEMI are: Dynamic ST/T changes ST depression > 0.5 mm in 2 or more contiguous leads T-wave inversion – deep symmetrical T-wave inversion Other ECG changes include new or presumed new onset bundle branch block (BBB)* and cardiac arrhythmias, especially sustained ventricular tachycardia. Evidence of previous infarctions such as Q waves may be present. However, a completely normal ECG does not exclude the diagnosis I, C of UA/NSTEMI. Serial ECGs should be done as the ST changes may evolve. * New LBBB should be treated as STEMI 4.4. Cardiac Biomarkers Cardiac troponins (troponin T or I) are the recommended I, A biomarkers. (Figure 3, pg 19) They are highly specific and sensitive for myocardial injury and/or necrosis (infarction), and also provide important prognostic information, there being a correlation between the level of troponin and cardiac mortality and other adverse cardiac events12-16. The troponin level may not be elevated if the test is done early (<6 hours). To confidently exclude myocardial necrosis (infarction), a repeat test needs to be done 6–12 hours after admission. Troponin testing can be done in the laboratory (quantitative) or with a hand held rapid semi-quantitative assay. Blood levels may persist for 5–14 days after the acute event. 17 Non coronary causes for elevated troponins are extremely rare . 17. It may o Non coronary causes for elevated troponins are extremely rare It acute occur in acute myocarditis, acute pulmonary embolism, aaneurysm may myocarditis, acute pulmonary embolism, a dissecting aortic heart failure and aneurysm, acute heart failureSevere renal dysfunction ma dissecting aortic sometimes in septic shock. and sometimes in cause raised troponins in the absence of ACS. A raised levelraised septic shock. Severe renal dysfunction may also cause is however asso with an increase in absence mortality in these patients. (Appendix II, pg 52) troponins in the all cause of ACS. A raised level is however associated with an increase in all cause mortality in these patients. (Appendix II, pg 52) 18 18
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Creatinine kinase (CK) and its MB fraction (CKMB) are also important indicators of myocardial and its MB fraction (CKMB) are also important Creatinine kinase (CK) necrosis (infarction). They are however, less sensitive and specific compared to cardiac troponins. CK are CKMB have indicators of myocardial necrosis (infarction). They and however, less a shorter and specific comparedare cardiac useful thanCK and CKMB have sensitive half life and hence to more troponins. troponins when a shorter half life and hence are more useful than troponins when diagnosing reinfarction. diagnosing reinfarction. All patients with NSTEMI have raised troponins, however, the CKMB may 18,19 be patients in 10-20% of have raised troponins, however, the CKMB may All normal with NSTEMI these patients . A raised CKMB in the presence of a normal troponin level has no prognostic significance 18,19. in the be normal in 10-20% of these patients 18,19. A raised CKMB presence of a normal troponin level has no prognostic significance 18,19. Myoglobin is not cardiac specific. It can be detected as early as 2 hours after the onsetnotchest pain. A negative test within 4-8 hours of chest 2 hours Myoglobin is of cardiac specific. It can be detected as early as pain is useful onset of chest pain. A negative test within 4-8 hours of chest pain after the in ruling out myocardial necrosis (infarction). It should not however bein ruling the only biomarker necrosis (infarction). It should not is useful used as out myocardial to identify patients with NSTEMI. however be used as the only biomarker to identify patients with NSTEMI. FIGURE 3: Time course of elevation of serum cardiac biomarkers in ACS FIGURE 3: Time course of elevation of serum cardiac biomarkers in ACS (Adopted from “Clinical Implications of the new definition of myocardial infarction”. John K French, Harvey D White; Heart 2004;90:99–106) 4.5 Other diagnostic modalities of the new definition of myocardial infarction”. John K French, (Adopted from “Clinical Implications 4.5 Other diagnostic modalities 2004;90:99–106) Harvey D White; HeartIIa, B Echocardiogram – LV systolic function is an important IIa, B Echocardiogram – LV systolic function is an important prognostic indicator in patients with UA/NSTEMI. Transient prognostic indicator in patients with UA/NSTEMI. Transient reversible regional wall motion abnormalities may be detected reversible regional wall motion abnormalities may be detected during ischemia. during ischemia. Key message: Key message: The diagnosis of UA/NSTEMI is based on history + dynamic ECG changes The diagnosis of UA/NSTEMI is based on history + dynamic ECG 19 (without persistent ST elevation), + raised cardiac biomarkers. (without persistent ST elevation), + raised cardiac biomarkers. In UA cardiac biomarkers are normal while in NSTEMI it is elevated. In UA cardiac biomarkers are normal while in NSTEMI it is elevate A raised troponin level has diagnostic and prognostic significance I,A. 19 A raised troponin level has diagnostic and prognostic significance 19
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 20115. RISK STRATIFICATION5.1 Assessment of RiskThe initial evaluation should be used to provide information about thediagnosis and prognosis. An attempt should be made to simultaneouslyanswer 2 questions: What is the likelihood that the signs and symptoms represent ACS? (Appendix III, pg 53) What is the likelihood of an adverse clinical outcome – death, MI (or recurrent MI), stroke, HF, recurrent symptomatic ischemia, and serious arrhythmia?In making a diagnosis of ACS one should consider the symptoms, ECGabnormalities and cardiac biomarkers. The absence of risk factors doesnot exclude a diagnosis of ACS.5.2 Rationale for Risk StratificationPatients with UA/NSTEMI have an increased risk of death, recurrent MI,recurrent symptomatic ischemia, serious arrhythmias, heart failure andstroke.Early assessment would help in determining the: prognosis of the patient management strategies - selection of the site of care (coronary care unit, monitored step-down ward or outpatient setting) - selection of appropriate therapy and the need for coronary angiogram and revascularization5.3 Risk Scores for prognosis of UA/NSTEMISeveral risk stratification scores have been developed and validated inlarge patient populations. In clinical practice, 2 risk scores that arecommonly used are: TIMI Risk Score 20,21 - it is less accurate in predicting events, but is simple and widely accepted. ( Appendix IV, pg 54) GRACE risk scores 22 (Appendix V, pg 55) 21 20
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Both risk scores confer additional important prognostic value beyondBoth risk scores confer additional important prognostic value beyondglobal risk assessment by physicians. These validated risk scores mayglobal risk assessment by physicians. These validated risk scores mayrefine risk stratification, thereby improving patient care in routine clinicalrefine risk stratification, thereby improving patient care in routine clinicalpractice 23. We have proposed a simplified risk stratification model aspractice 23. We have proposed a simplified risk stratification model asoutlined in Flowchart 1, pg 3.outlined in Flowchart 1, pg 3.5.4 Risk Assessment for Bleeding5.4 Risk Assessment for BleedingHemorrhagic complications are an independent risk factor for subsequentHemorrhagic complications are an independent risk factor for subsequentmortality in ACS patients and in those undergoing PCI. These patients canmortality in ACS patients and in those undergoing PCI. These patients canbe identified by:be identified by: ACUITY HORIZONS-AMI24 Bleeding Risk Score ACUITY HORIZONS-AMI24 Bleeding Risk Score CRUSADE Bleeding Risk Score25 CRUSADE Bleeding Risk Score25These scores are calculated based on age, clinical status andThese scores are calculated based on age, clinical status andhemodynamics at presentation, serum creatinine and hematocrit level andhemodynamics at presentation, serum creatinine and hematocrit level andthe use and combinations of antiplatelets and anticoagulants.the use and combinations of antiplatelets and anticoagulants.Key messagesKey messages Risk stratification is important for prognosis and to guide Risk stratification is important for prognosis and to guide management I,A. management I,A.6. TRIAGE6. TRIAGETriage helps in identifying patients who need urgent care. RapidTriage helps in identifying patients who need urgent care. Rapidassessment and aggressive management of high risk patients may resultassessment and aggressive management of high risk patients may resultin an improvement in outcome and a reduction in mortality.in an improvement in outcome and a reduction in mortality.Rapid assessment includes:Rapid assessment includes: evaluation of patient’s clinical status: evaluation of patient’s clinical status: - mental status - mental status - comfort status - comfort status - respiration - respiration - peripheral perfusion - peripheral perfusion vital signs: vital signs: - blood pressure - blood pressure - rate and volume of pulse - rate and volume of pulse - respiratory rate - respiratory rate history: history: - presence and severity of chest pains - presence and severity of chest pains 22 22 21
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 - past history of coronary and vascular events, interventions and surgery - risk factors  hypertension  diabetes mellitus  dyslipidaemia  previous medications – eg anti-anginals, antiplatelets  family history of premature CAD ECG cardiac biomarkers - troponins - CK-MBBased on the above clinical assessment, patients can be risk stratified to(Flowchart 1, pg 3) : I. Intermediate/high risk II. Low riskThe TIMI Risk Score and the Grace Risk Score (see 5.3) are also used toprovide additional prognostic information.The appropriate management, which includes the rapidity and the degreeof invasiveness, is generally guided by the risk status of the patient. Thereis evidence that high risk patients have increasing benefit from therapies(like low molecular weight heparin (LMWH), glycoprotein (GP) IIb/IIIainhibitors) and an invasive strategy.The recommended therapy based on risk-stratification is as in Flowchart1, pg 3. Key messages Intermediate/high risk patients benefit from early angiography and revascularization I,A.7. Management of UA/NSTEMIThe goals of management are: Immediate relief of ongoing ischemia and angina Prevention of recurrent ischemia and angina Prevention of serious adverse cardiac events 23 22
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 7.1 Pre-hospital Management 7.1 Pre-hospital Management Based on the triage: 7.1 Pre-hospital Management Based on the triage: Based If the history is suggestive of ACS :  on the triage: - Give soluble aspirin 300 ACS :  If the history is suggestive of mg crushed stat - Give sublingual GTN  If the history is suggestive of mg crushed stat soluble aspirin 300 ACS : - Do 12 lead ECGGTN cardiaccrushed stat Give soluble aspirin 300 mg biomarkers sublingual and - Do 12 lead ECGGTN cardiac biomarkers Give sublingual and - Do 12 lead ECG and cardiac biomarkers If the ECG and cardiac biomarkers are suggestive of ACS - Give clopidogrel 300 mg stat if available. If the ECG and cardiac biomarkers are suggestive of ACS -- Give clopidogrel 300 mg stat if are suggestive of where If the ECG and cardiac to the nearest healthcare facility ACS Send the patient biomarkers available. definitive treatment can be given. -- Give clopidogrel 300the nearest healthcare facility where Send the patient to mg stat if available. - Send the treatment can nearest healthcare facility where definitive patient to the be given. definitive treatment can be given. If the ECG and cardiac biomarkers are inconclusive for ACS If the- ECG and cardiac biomarkers are inconclusive for ACS Low risk patients : they can be referred as outpatient If the- ECGcardiacpatients : they canare inconclusive for ACS for and cardiac biomarkers1, be 5) Low risk assessment. (Fig pg referred as outpatient - Low risk patients : Risk can be 5) should be admitted Intermediate / High they patients : for cardiac assessment. (Fig 1, pg referred as outpatient . - for cardiac assessment. (Fig 1, pg 5) should be admitted Intermediate / High Risk patients : - - Intermediate / High Risk patients : should be admitted . 7.2 In-Hospital Management (Table1, pg 4) - . - 7.2 In-Hospital Management (Table1, pg 4) 7.2 Initial management – General Measures 7.2.1 In-Hospital Management (Table1, pg 4) 7.2.1 Initial management – General Measures 7.2.1 Initial management – General Measures Following risk stratification: Following risk stratification: low risk patients may be treated as outpatient. Following risk stratification: low risk patients may be treated as outpatient. I, C High risk patients preferably should be admitted to CCU/HDU low risk patients may be treated as outpatient. I, C High risk patients preferably should be admitted to CCU/HDU with continuous ECG monitoring. I, C Highcontinuous ECG monitoring. with risk patients preferably should be admitted to CCU/HDU supplemental oxygen monitoring.given to maintain SpO2 >90%, with continuous ECG should be I, B in patients with left ventricular failure, respiratorySpO2 >90%, supplemental oxygen should be given to maintain distress or I, B having high with features for hypoxemia. respiratorySpO2 >90%, in patients risk left ventricular failure, maintain distress or supplemental oxygen should be given to I, B in patients with features for hypoxemia. respiratory distress or having high risk left ventricular failure, having high riskmorphine for hypoxemia. mg to 5 mg) together for pain relief, features (intravenous 2IIa,B withpain relief, morphine (intravenous 2 mg to 5given.together for concomitant intravenous anti-emetic may be mg)IIa,B for pain relief, morphine (intravenous 2 mg to 5given.togetherIIa,B with concomitant intravenous anti-emetic may be mg) 7.2.2. Medications - Antiplatelet agents with concomitant intravenous anti-emetic may be given. 7.2.2. Medications - Antiplatelet agents 7.2.2.1 Oral antiplatelet agents 7.2.2. Medications - Antiplatelet agents 7.2.2.1 Oral antiplatelet agents 7.2.2.1.1 Oral antiplatelet agents 7.2.2.1 Acetylsalicylic acid (ASA) 7.2.2.1.1 Acetylsalicylic acid (ASA) I, A 7.2.2.1.1 Acetylsalicylic acid (ASA) 300 mg of soluble/chewable Recommended loading dose: I, A aspirin 26,27. Enteric coated aspirin is not recommended for Recommended loading dose: 300 mg of soluble/chewable I, A initial loading Enteric coatedofaspirin isonset recommended for Recommended loading dose:it’s slow not of action. aspirin 26,27. dose because 300 mg of soluble/chewable aspirin 26,27. dose because it’s slow not of action. initial loading Enteric coatedofaspirin isonset recommended for 24 initial loading dose because of it’s slow onset of action. 24 24 23
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 I, A Maintenance dose: 75-150 mg daily of soluble or enteric coated aspirin 26,27 Aspirin in excess of 300-325 mg per day is associated with increased risk of minor bleeding without greater efficacy 27. 7.2.2.1.2 Adenosine Diphosphate (ADP) Receptor Antagonists These include: I, A Clopidogrel – loading dose: 300 to 600 mg, maintenance dose: 75 mg/day 28,29IIa, B Ticlopidine – dose: 250 mg b.i.d. It is associated with neutropenia in 1% of patients 30. Due to this safety reason, it is not preferred. Patients on ticlopidine should have their total white cell count monitored regularly for the initial 3 months.I, B Prasugrel – loading dose 60 mg, maintenance dose: 10 mg/day - To date, outcome data is only available in ACS patients undergoing PCI 31. It is recommended to be given after coronary angiography in patients planned for PCI. - Its use in other subsets of patients is still being evaluated. - It is not recommended for patients >75 years old, <60 kg weight, past history of transient ischemic attack or stroke due to a higher risk of major bleeding. I, B Ticagrelor – loading dose : 180 mg, maintenance dose : 90 mg bid. - Ticagrelor was shown to significantly reduce cardiovascular endpoints when compared to clopidogrel in patients with ACS 32. - This agent is short acting and thus can be used in patients who may need surgery without increasing the risk of bleeding. - Potential drawback is dyspnoea and transient ventricular pauses during the first week. This was rarely associated with symptoms or need for a pacemaker. There was also a small increase in non CABG related major bleeding32. 25 24
    • Clinical Practice Guidelines on with symptoms or need for a pacemaker. There was also a management of Unstable Angina/Non 32 ST small increase in non CABG related major bleeding .Elevation Myocardialneed for a pacemaker. There was also a with symptoms or Infarction (UA/NSTEMI) 20117.2.2.2 Intravenous Antiplatelet Therapy major bleeding 32. (GP) small increase in non CABG related – GlycoproteinIIb/IIIa Inhibitors7.2.2.2 Intravenous Antiplatelet Therapy – Glycoprotein (GP)IIb/IIIa These include: Inhibitors Abciximab These include: Tirofiban Abciximab Eptifibatide Tirofiban Eptifibatide These agents may be used in high risk patients awaiting transfer to a PCI facility for an early invasive strategy. Its routine use as These agents may prior to in is now no longer practiced 33,34. “upstream therapy” be usedPCIhigh risk patients awaiting transfer to a PCI facility for an early invasive strategy. Its routine use as 33,347.2.3. Anticoagulant Therapy PCI is now no longer practiced “upstream therapy” prior to .7.2.3. Anticoagulant (Table 2, pg 27) These include: TherapyI, A These include: (Table 2, pg 27) Unfractionated heparin (UFH)I, A Unfractionated heparin (UFH)I, A Low Molecular Weight Heparin (LMWH)-Enoxaparin 35,36,37 Anti Xa inhibitor-FondaparinuxI, A Low Molecular Weight Heparin (LMWH)-Enoxaparin 35,36,37I, A Anti Xa inhibitor-Fondaparinux - It is best used in UA/NSTEMI patients treated conservatively 38,39.I, A - It is associated with an increase in patients treated is best used in UA/NSTEMI catheter-related conservatively 38,39. thrombus and coronary angiographic complications. - It is associated with an increase sole anticoagulant is not recommended as the in catheter-related during PCI 38,39 coronary angiographic complications. thrombus and . - It used in recommendedand the patient requires an If is not UA/NSTEMI as the sole anticoagulant during PCI 38,39. UFH should be given during the invasive strategy, - If used in UA/NSTEMI and the itpatient requireswith procedure. When used in PCI, is associated an lower bleeding rates than LMWH 38,39,40. invasive strategy, UFH should be given during the procedure. When used in PCI, it is associated with 38,39,40 Presently newer oralrates than LMWH lower bleeding anti Xa inhibitors are undergoing . evaluation for ACS. Presently newer oral anti Xa inhibitors are undergoing evaluation for ACS. Anti IIa inhibitors – BivalirudinI, B - may be – Bivalirudin Anti IIaItinhibitors used as a substitute for heparin in patients with heparin-induced thrombocytopenia (HIT) 41.I, B - It is reasonable as use bivalirudin as an alternative to may be used to a substitute for heparin in patients 41I, A UFH and GP IIb/IIIa thrombocytopenia (HIT) . with heparin-induced inhibitors in patients undergoing - It is reasonable to use bivalirudin as an alternative to PCI 42-45.I, A - UFH and GP IIb/IIIaless bleeding. It is associated with inhibitors in patients undergoing 42-45 - PCITo date . is not yet available in Malaysia. it - It is associated with less bleeding. - To date it is not yet available in Malaysia. 26 26 25
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Key messages High risk patients preferably should be continuously monitored in CCU/HDU I,C. Intermediate/high risk patients should be given ASA I,A,clopidogrel I,A (or prasugrel I,B or ticagrelor I,B) and UFH I,A or LMWH I,A or fondaparinux I,A. Prasugel may be given after coronary angiography in high risk patients undergoing PCI I,B. (Table 1, pg 4) Low risk patients should be given aspirin I,A and risk stratified as outpatient with non invasive tests for reversible ischemia. (Fig 1, pg 5) 27 26
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011TABLE 2: Doses of Anticoagulant Agents in UA/NSTEMI and during PCI*35-39,42-45AGENT DOSING REGIMENUFHUA/NSTEMI Initial IV bolus : 60 IU/kg (max 4000 IU) followed by infusion of 12 IU/kg/hour (max 1000 IU/hour) adjusted to maintain aPTT 1.5-2.0x normal. Duration of therapy : 2-8 days35-37During PCI Loading Dose : Empirical loading dose: 5000-10000 IU, or Weight adjusted loading dose: - Not receiving GP IIb/IIIa inhibitors: 70-100 IU/kg - Receiving GP IIb/IIIa inhibitors : 50-70 IU/kg Further doses if procedure is > 1 hour may be by: Empirical weight adjusted doses : - Not receiving GP IIb/IIIa inhibitors: 60 IU/kg - Receiving GPIIb/IIIa inhibitors: 50 IU/kg Guided by ACT monitoring - Not receiving GP IIb/IIa inhibitors maintain ACT: 250-300 secs - Receiving GP IIb/IIIa inhibitors maintain ACT: 200 secsEnoxaparinUA/NSTEMI Initial 30 mg IV bolus and then 15 minutes later by: sc 1.0 mg/kg every 12 hours if age less than 75 years sc 0.75 mg/kg every 12 hours if age 75 years and above Duration of therapy : 2-8 days 35-37During PCI Depends on prior enoxaparin use: No prior use : 0.5-0.75 mg/kg IV bolus Prior use within 8 hours of PCI: no additional dose Prior use between 8-12 hours of PCI: 0.3 mg/kg IV. Supplemental UFH may also be given during PCIBivalirudinUA/NSTEMI 0.1 mg/kg bolus and 0.25 mg/kg/hour infusionDuring PCI Depends on prior bivalirudin/UFH use: Prior treatment with bivalirudin: additional 0.5 mg/kg bolus and increase infusion rate to 1.75 mg/kg/hour Prior treatment with UFH: wait 30 mins then 0.75 mg/kg bolus and infusion of 1.75 mg/kg/hour No prior treatment: 0.75 mg/kg bolus and infusion of 1.75 mg/kg/hourFondaparinuxUA/NSTEMI 2.5 mg sc daily for 8 days or duration of hospitalization 38,39During PCI If used during PCI, additional 50-60 IU/ kg UFH is recommended.* For doses in renal impairment see section 9.3, Table 6, pg 35 28 27
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 7.2.4 Anti-Ischemic Drug Therapy These agents may be given either for relief of ischemia (symptoms) or for prognosis. 7.2.4.1 Nitrates (Table 3, pg 29)I, C Sublingual glyceryl trinitrate (GTN 0.5 mg) – Patients with UA/NSTEMI with ongoing chest pain should receive sublingual GTN 0.5 mg every 5 minutes for a total of 3 doses. If symptoms still persist, intravenous GTN should be considered.I, C Intravenous nitrates – may be administered in the following situations: No symptom relief after 3 doses of sublingual GTN Presence of dynamic ECG changes Presence of left ventricular failure Concomitant high blood pressure. Oral nitrates may be given after 12 to 24 hours of pain free period. Rebound angina may occur with abrupt cessation of nitrates 46. Contraindications to nitrate therapy: Hypotension (SBP< 90 mmHg) RV infarction History of phospho-diesterase 5 inhibitors ingestion (depending upon the half-life of the agent) 7.2.4.2 β-blockers (Table 4, pg 29)I, B In the absence of contraindications, β-blockers should be administered early. Contraindications for β-blockers in UA/NSTEMI 47 : Patients with marked first-degree AV block (PR interval greater than 0.24s). Second- or third-degree AV block. History of bronchial asthma Severe peripheral arterial disease Acute decompensated LV dysfunction Cardiogenic shock. 29 28
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Table 3: Recommended dosages of Nitrates in UA/NSTEMI* Compound Route Dosage Time of Onset Table 3: Recommended dosages of Nitrates in UA/NSTEMI* 0.3 - 0.6 mg, can repeat up Compound Sublingual Route to 3 times at 5 minute Dosage 2 minute Time of Onset intervals 0.3 - 0.6 mg, can repeat up Intravenous Sublingual 5 – 200 at 5 minute to 3 timesµg/min* 1 2 minute minuteNitroglycerine, intervals 0.4 – 0.8 mg per metered Glyceryl trinitrate dose, no more than 3 Intravenous GTN Spray 5 – 200 µg/min* 2 1 minute minute Nitroglycerine, sprays at 5 minute Glyceryl intervals 0.4 – 0.8 mg per metered trinitrate dose, no more than 3 GTN Spray 2.5 – 20 mg over 12 hours 2 minute Transdermal patch sprays at 5 minute 1 – 2 hours on, then 12 hours off intervals Intravenous 2 – 12 mg / hour 1 minute 2.5 – 20 mg over 12 hours Isosorbide Transdermal patch 1 – 2 hours dinitrate 10 on, then 12 – 3 times – 20 mg, 2 hours off Oral 30 – 60 minutes daily Intravenous 2 – 12 mg / hour 1 minute Isosorbide Isosorbide dinitrate Oral (LA) 10 30-60mg, 2 – 3 times – 20 mg daily, mononitrate Oral ( max 120 mg ) 30 – 60 minutes daily *The dose of IV nitrates should be titrated every 5 – 10 minutes until symptoms and/or Isosorbide Oral (LA) 30-60 mg daily, ischaemia is relieved and the desired haemodynamic response is obtained mononitrate ( max 120 mg ) *As stated in MIMS Malaysia *The dose of IV nitrates should be titrated every 5 – 10 minutes until symptoms and/or ischaemiaRecommended dosages of β -blockers in UA/NSTEMI* Table 4: is relieved and the desired haemodynamic response is obtained *As stated in MIMS Malaysia Type Initiation dose Target dose Table 4: Recommended dosages of β -blockers in UA/NSTEMI* Metoprolol 25 mg bd 100 mg bd Type Atenolol Initiation dose 25 mg od 100 mg dose Target od Metoprolol Bisoprolol 25 mg bd 1.25 mg od 10 mg odbd 100 mg Atenolol Carvedilol 3.125 mg od 25 mg bd 25 mg bdod 100 mg Bisoprolol *As stated in MIMS Malaysia 1.25 mg od 10 mg od Carvedilol 3.125 mg bd 25 mg bd *As stated in MIMS Malaysia 30 30 29
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 7.2.4.3 Calcium Channel Blockers (Table30) 5, pg 7.2.4.3 Calcium Channel Blockers pg 5, 7.2.4.3 Calcium Channel Blockers (Table 5, (Tablepg 30)30) Calcium channel blockers (CCB) may be used in UA/NSTEMI in the in the the Calcium channel blockers (CCB) may be be used UA/NSTEMI Calcium channel blockers (CCB) may used in in UA/NSTEMI in following situations: following situations: following situations:I, B B I, B I, Verapamil or diltiazem as an alternative to patientsto patients who are not Verapamil or diltiazem as an an alternative patients who are not Verapamil or diltiazem as alternative to who are not able to tolerate or who who have contraindication to β –blockers.48 48 able to tolerate or have contraindication to β –blockers.48 able to tolerate or who have contraindication to β –blockers.IIa,C IIa,C Continuing or recurring angina despite adequate adequate doses of IIa,C Continuing or or recurring angina despite doses of Continuing recurring angina despite adequate doses of nitrates andand β-blockers – verapamil, diltiazem,release release nitrates β-blockers – verapamil, diltiazem, diltiazem, slow release nitrates and β-blockers – verapamil, slow slow nifedipine andand amlodipine. nifedipine amlodipine. nifedipine and amlodipine. Prinzmetal’s angina (variant angina) angina) Prinzmetal’s angina (variant angina) Prinzmetal’s angina (variantIII, A A A Short-acting dihydropyridine CCB should be avoided III, III, Short-acting dihydropyridine CCB should be avoided avoided Short-acting dihydropyridine CCB should be TableTableRecommended dosages of Calcium Channel Blockers in UA/NSTEMI* Table 5: 5: Recommended dosages of Channel Blockers in UA/NSTEMI* 5: Recommended dosages of Calcium Calcium Channel Blockers in UA/NSTEM Drug Drug Drug Dose Dose Dose Diltiazem Diltiazem Diltiazem Immediate release 30-90 mg tds mg mg tds Immediate release 30-90 Immediate release 30-90 tds Slow Slow release 100-200 mg mg od release 100-200 mg od Slow release 100-200 od Verapamil Verapamil Verapamil Immediate release 40-80 mg tds mg mg tds Immediate release 40-80 Immediate release 40-80 tds Slow Slow release 120-240 mg mg od Slow release 120-240 od release 120-240 mg od Amlodipine Amlodipine Amlodipine 2.5-10 mg od mg od 2.5-10 mg od 2.5-10 Nifedipine Nifedipine Nifedipine Slow Slow release 30-90 mg mg od release 30-90 mg 30-90 od Slow release od *As stated in MIMSin MIMS Malaysia *As *As stated Malaysia stated in MIMS Malaysia 7.2.5 7.2.5 Modifying Drugs Drugs 7.2.5 Lipid Modifying Drugs Lipid Lipid Modifying Current data indicate that that early initiation of high dose statin therapy Current data indicate early initiation of high dose high dose statin therapy Current data indicate that early initiation of statin therapyI, A I, A soon soon admission for UA/NSTEMI can reducereduce adverse adverseA soon after admission for for UA/NSTEMI can reduce major adverse after after admission UA/NSTEMI can major major cardiac eventsevents its pleotropic effects49-54. Patients .with ACS with ACS cardiac events due to its pleotropic effects49-54. Patients with ACS cardiac due to due to its pleotropic effects49-54 Patients undergoing PCI, have also also been found to towith the with the undergoing PCI, have been found to found benefit with the undergoing PCI, have also been benefit benefit administration of highhigh dose statins before and 10 days10 days of the the administration of of high dose statins before and within 10 days of administration dose statins before and within within of the procedure 55-57. 55-57. procedure 55-57. procedure The statinsstatins that have beenin UA/NSTEMI to date to date are: The statins that have been studied in UA/NSTEMI are: date are: The that have been studied studied in UA/NSTEMI to Atorvastatin – 80 mg od mg od Atorvastatin – 80 mg od Atorvastatin – 80 Simvastatin – 40 mg od mg od Simvastatin – 40 mg od Simvastatin – 40 31 31 31 30
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 7.2.6 Angiotensin Converting Enzyme Inhibitor (ACE-I)/ARB (Table 7.2.6 Angiotensin Converting Enzyme Inhibitor (ACE-I)/ARB (Table 7,7, pg 39) pg 39) These should be considered early for patients with LV dysfunction These should be considered early for patients with LV dysfunctionI, A A I, and diabetes 5555. and diabetes . Key messages Key messages Patients should be treated with optimal medical therapy. Patients should be treated with optimal medical therapy. (Table 1,1, pg 4) (Table pg 4) Nitrates I,CI,C,β-blockers I,BI,B+ +CCBs I,CI,Care given for relief ofof Nitrates , β-blockers CCBs are given for relief ischemia. ischemia. Statins I,AI,A I,A Statins and ACE-I (for LV dysfunction, LVEF < < 40%) I,A are and ACE-I (for LV dysfunction, LVEF 40%) are given for prognosis. given for prognosis. 8. Revascularization Strategies 8. Revascularization Strategies There is a strong rationale for early revascularization in There is a strong rationale for early revascularization in intermediate/high risk patients with UA/NSTEMI 56,57. (Flowchart 1, intermediate/high risk patients with UA/NSTEMI 56,57. (Flowchart 1, pg 3, Appendix IV, pg 54) Contemporary antiplatelet and pg 3, Appendix IV, pg 54) Contemporary antiplatelet and anticoagulant therapies have reduced the early hazard of PCI. anticoagulant therapies have reduced the early hazard of PCI. With increasing procedure experience, technological improvements inWith increasing procedure experience, technologicalanticoagulant PCI and the development of new antiplatelet and improvements regimens there development of new antiplatelet and anticoagulant in PCI and the is a general trend for early revascularization in these patients following general medical therapy. revascularization in regimens there is a optimal trend for early these patients following optimal medical therapy. 8.1. Routine early invasive management 58-61 8.1. Routine early invasive management 58-61 I, B Urgent (as soon as possible after hospital presentation) 62 – 62 I, B Urgent angiography/revascularization for patients with – coronary (as soon as possible after hospital presentation) refractory orangiography/revascularization for patients ST coronary recurrent angina associated with dynamic with deviation, heartrecurrent life threatening arrhythmias and/ or refractory or failure, angina associated with dynamic ST deviation, heart failure, life threatening arrhythmias and/ or hemodynamic instability hemodynamic instability I, A Early (<72 hours) coronary angiography/revascularization- in I, A patients(<72 hours) coronary angiography/revascularization- in Early with high-risk features as predicted by a positive biomarker with high-risk features as predicted by risk positive patients assay, ST segment changes or a high a score 58-61 according to assay, ST segment changes or a high risk score biomarker the TIMI scale or equivalent . according to the TIMI scale or equivalent 58-61.IIb, B Routine invasive evaluation is not recommended in low risk patients 58-61. Routine invasive evaluation is not recommended in low risk IIb, B patients 58-61. However these patients are recommended to have non-invasive assessment for inducible or silent ischemia. to have non-invasive However these patients are recommended assessment for inducible or silent32 ischemia. 32 31
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 8.2 8.2Routine early conservative management (selective invasive Routine early conservative management (selective invasive therapy) 63,64,65 therapy) 63,64,65I, A I, A TheThe use of aggressive anticoagulantantiplatelet agents has has use of aggressive anticoagulant and and antiplatelet agents alsoalso reduced incidence of adverse outcomes in patients reduced the the incidence of adverse outcomes in patients managed conservatively63,64,65. managed conservatively63,64,65. Selective Selectivecoronary coronary angiography/revascularization is indicated for those thosecannotcannot angiography/revascularization is indicated for who who be be stabilized medically in whom objective evidence of stabilized medically or or in whom objective evidence of significant ischemia is provoked in thein the sub acute phase. significant ischemia is provoked sub acute phase. A conservative strategy is recommended for women who are are A conservative strategy is recommended for women whoIIa, A A IIa, stabilized and and remain biomarker negative 66. stabilized remain biomarker negative 66. An early invasive or conservative therapy is a reasonable option option An early invasive or conservative therapy is a reasonableIIa, A A IIa, for menmen who stabilized and remain biomarker negative 66. for who are are stabilized and remain biomarker negative 66. Patients with with UA/NSTEMI treated conservatively are at risk of Patients UA/NSTEMI treated conservatively are at risk of developing recurrent adverse cardiac events. Thus Thus these developing recurrent adverse cardiac events. these patients need to be evaluated patients need to be evaluated periodically for reversible periodically for reversible ischemia using non non invasive tests. If ischemia is present, they ischemia using invasive tests. If ischemia is present, they should be be considered for coronary angiography and should considered for coronary angiography and revascularization. revascularization. Key messages Key messages Patients with with refractory angina and/ or hemodynamically unstable Patients refractory angina and/ or hemodynamically unstable should be be considered urgent coronary angiography and and should considered for for urgent coronary angiography revascularization I,C. I,C. revascularization Intermediate/high risk risk patients should considered for early early Intermediate/high patients should be be considered for invasive strategy hours) I,A. If I,A. If admitted to a non-PCI centre, invasive strategy (<72(<72 hours) admitted to a non-PCI centre, they they should be considered for transfer to a PCI centre I,B. (Flowchart 1, should be considered for transfer to a PCI centre I,B. (Flowchart 1, pg 3) 3) pg LowLow risk patients should be assessed non-invasively for ischemia I,C. risk patients should be assessed non-invasively for ischemia I,C. (Fig(Fig 1,5) 5) 1, pg pg 9 9 UA/NSTEMI IN SPECIAL GROUPS UA/NSTEMI IN SPECIAL GROUPS All patients should receive optimal medical therapy. (Table(Table4) pg 4) All patients should receive optimal medical therapy. 1, pg 1, 9.1 9.1UA/NSTEMI in the Elderly UA/NSTEMI in the Elderly Cardiovascular morbidity and mortality increases by 70% for every every 10 Cardiovascular morbidity and mortality increases by 70% for 10 year increase in age18,67-68. year increase in age18,67-68. 33 33 32
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 9.1.1 9.1.1 Clinical presentation: Clinical presentation: AA high index of suspicion is necessary to make a diagnosis of high index of suspicion is necessary diagnosis of UA/NSTEMI in elderly patients. Atypical presentations occur more UA/NSTEMI in elderly patients. Atypical presentations more frequently. These include: frequently. These include: dyspnoea dyspnoea diaphoresis diaphoresis nausea and vomiting nausea and vomiting neurological symptoms such as acute confusional states and neurological symptoms such as acute states and syncope syncope ACS frequently develops as a “secondary” coronary event in the setting ACS frequently develops as a “secondary” coronary setting of another acute illness e.g. pneumonia. The elderly often are in heart of another acute illness e.g. pneumonia. The heart failure at the time of presentation 69.. The ECG‘s may be non diagnostic. failure at the time of presentation 69 The ECG‘s diagnostic. 9.1.2. Management 9.1.2. Management There is limited trial data to guide management in the elderly especially There is limited trial data to guide management especially in the setting of advanced age (more than 75 years) or significant co- in the setting of advanced age (more than significant co- morbidity (e.g. prior stroke, renal impairment). One should consider the morbidity (e.g. prior stroke, renal impairment). consider the biological age rather than the chronological age of the patient when biological age rather than the chronological when making management decisions. The elderly are a heterogenous group making management decisions. The elderly group and the risk benefit ratio of each intervention should be individualized. and the risk benefit ratio of each intervention individualized. Creatinine clearance should be calculated to enable appropriate drug Creatinine clearance should be calculated drug dosing. (Appendix VI,pg 56) dosing. (Appendix VI,pg 56)I, I, A A Both aspirin and clopidogrel (especially in those undergoing PCI) Both aspirin and clopidogrel (especially undergoing PCI) confer greater absolute and relative benefits in the elderly 70,71.. confer greater absolute and relative benefits 70,71I, I, B B Prasugrel should be avoided in patients older than 75 years in Prasugrel should be avoided in patients years in view of the bleeding risk 31.. view of the bleeding risk 31I, I, A A In aameta-analysis, both UFH and LMWH were equally effective in In meta-analysis, both UFH and LMWH effective in the elderly 72. .However bleeding risk is higher with both agents. the elderly 72 However bleeding risk is agents.I, I, B B Elderly patients have more bleeding complications with the use of Elderly patients have more bleeding complications use of GPIIb/IIIa inhibitors 73,74.. If required, the dose should be adjusted GPIIb/IIIa inhibitors 73,74 If required, the adjusted according to the renal function. according to the renal function.I, I, A A The elderly have greater in-hospital and long term benefits with The elderly have greater in-hospital benefits with an early invasive strategy 75-79.. In some trials, all the benefits of an an early invasive strategy 75-79 In some of an early invasive strategy were in the elderly rather than in younger patients 75. However there is an increased risk of major bleeding 80. 34 34 When selecting patients for an early invasive strategy, the risk benefit ratio must be considered. For patients with multi vessel 33 disease and not suitable for CABG, partial revascularization of the
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevationinvasivestrategy were ininthe elderly rather than in2011 early Myocardial Infarction (UA/NSTEMI) in younger early invasive strategy were in the elderly rather than in younger early invasive strategy were the elderly rather than patients 7575However there isisan increased risk of major bleeding 80. . patients 75.. . Howeverthere is an increased risk of major bleeding 80 patients However there an increased risk of major bleeding When selecting patients for an early invasive strategy, the risk When selecting patients for an early invasive strategy, the risk When selecting patients for an early invasive strategy, benefit ratio must be considered. For patients with multi vessel benefit ratio must be considered. For patients with multi vessel benefit ratio must be considered. For patients with multi disease and not suitable for CABG, partial revascularization of the disease and not suitable for CABG, partial revascularization of the disease and not suitable for CABG, partial revascularization culprit lesion may be a aconsideration. culprit lesion may be a consideration. culprit lesion may be consideration. Long term management post discharge should include Long term management post discharge should include Long term management post discharge should medications that have been proven beneficial in secondary medications that have been proven beneficial in secondary medications that have been proven beneficial in secondary prevention. prevention. prevention. 9.2 9.2 UA/NSTEMI in Women UA/NSTEMI in Women UA/NSTEMI in Women Women develop CAD about a adecade later than men at aatime when Women developCAD about a decade later than men at a time when develop CAD about decade later than men at time they are older and have more co-morbidity such as obesity, diabetes, they are olderand have more co-morbidity such as obesity, diabetes, older and have more co-morbidity such as obesity, diabetes, hypertension and osteoarthritis 8181. However gender is not an hypertension and osteoarthritis 81. However gender is not an hypertension and osteoarthritis . However gender is not independent predictor ofof11year survival. independent predictor of 1 year survival. independent predictor year survival. 9.2.1 Clinical Presentation 9.2.1 Clinical Presentation Clinical Presentation Women presenting with ACS often have atypical symptoms such Women presenting with ACS often have atypical symptoms such Women presenting with ACS often have atypical symptoms as neck and shoulder ache and dyspnoea. Often, women have asneck and shoulder ache and dyspnoea. Often, women have neck and shoulder ache and dyspnoea. Often, women non specific ECG changes such as TTwave changes even in the nonspecific ECG changes such as T wave changes even in the specific ECG changes such as wave changes even absence ofofheart disease, thus making the diagnosis of CAD absence of heart disease, thus making the diagnosis of CAD absence heart disease, thus making the diagnosis of difficult. difficult. difficult. 9.2.2 9.2.2 9.2.2 Management Management Management InIn general,there are no gender specific differences in the efficacy general, there are no gender specific differences in the efficacy general, there are no gender specific differences in the efficacy ofofthe commonly used drugs in ACS. The following are some the commonly used drugs in ACS. The following are some the commonly used drugs in ACS. The following are important differences: important differences: important differences:I, B B I, Prasugrel isisassociated with more bleeding in individuals who Prasugrel associated with more bleeding in individuals Prasugrel is associated with more bleeding in individuals who are less than 60kg ininweight 3131. are less than 60kg in weight 31. are less than 60kg weight . I, B B I, A A meta-analysis indicates aa lack of benefit of GPIIb/IIIa meta-analysis indicates lack of benefit of GPIIb/IIIa meta-analysis indicates a lack of benefit of GPIIb/IIIa inhibitors inin women82.. The bleeding risk isis alsohigher. inhibitors in women 8282.The bleeding risk isalso higher. inhibitors women The bleeding risk also higher.IIa, A A IIa, There isisconflicting data regarding the benefits of an early There conflicting data regarding the benefits of an There is conflicting data regarding the benefits of an early invasive strategy ininwomen with UA/NSTEMI 66,84-86. ..Until this invasive strategy in women with UA/NSTEMI 66,84-86 Until this invasive strategy women with UA/NSTEMI 66,84-86 Until issue isisresolved ininrandomized controlled trials, an invasive issue is resolved in randomized controlled trials, an invasive issue resolved randomized controlled trials, an invasive strategy isisbest reserved for women with ongoing ischemia and strategy is best reserved for women with ongoing ischemia and strategy best reserved for women with ongoing ischemia raised troponins. raised troponins. raised troponins. 9.3 UA/NSTEMI in Chronic Kidney Disease (CKD) In patients with ACS, the presence of CKD is an additional high- 35 35 35 risk feature associated with increased mortality, the more severe 87-90 the CKD, the higher the mortality . The creatinine clearance can be calculated using the Cockroft- 34 Gault formula (Appendix VI, pg 56). Drug doses should be I, B adjusted according to renal function.
    • 9.3 UA/NSTEMI in Practice Guidelines on Clinical Chronic Kidney Disease (CKD) management of Unstable Angina/Non ST In patients with ACS, the presence of CKD is an additional high- Elevation Myocardial Infarction (UA/NSTEMI) 2011 risk feature associated with increased mortality, the more severe the CKD, the higher the mortality.87-90 The creatinine clearance can be calculated using the Cockroft- Gault formula (Appendix VI, pg 56). Drug doses should be I, B adjusted according to renal function. Patients with renal impairment were excluded from most clinical trials. In general, the management of patients with CKD is similar to those with normal renal function except for the following differences: Patients with CKD have more co-morbidity. ACE-I and ARB may cause worsening renal function and hyperkalemia. They are at increased bleeding risks. The doses of antithrombotic agents need to be adjusted accordingly to avoid excessive bleeding (Table 6, pg 35). Bivalirudin and I, B fondaparinux seem to be associated with less bleeding than heparin or enoxaparin 45,91. A recent meta-analysis showed that patients with CKD IIa, B presenting as UA/NSTEMI and treated with an early invasive strategy had better outcomes particularly in patients with mild to moderate renal insufficiency 92,93. PCI in patients with CKD is associated with increased risks of: bleeding worsening renal function and acute on chronic renal failure due to contrast nephropathy and/or cholesterol embolisation. Strategies should be taken to reduce this risk. (Appendix VII, pg 56 and VIII, pg 57) Table 6: Dosages of Anti-thrombotics in CKD* Table 6: Dosages of Anti-thrombotics in CKD* LOADING DOSE MAINTENANCE DOSE LOADING DOSE MAINTENANCE DOSE UFH No change No change UFH No change No change Enoxaprin 30 mg IV 1 mg/kg sc every 24 hours if Enoxaprin 30 mg IV 1 mg/kg sc every 24 hours if CrCl < 30 ml/min CrCl < 30 ml/min Fondaparinux Avoid if Cr Cl < 30 ml/min Avoid if Cr Cl < 30 ml/min Fondaparinux Avoid if Cr Cl < 30 ml/min Avoid if Cr Cl < 30 ml/min Eptifibatide 180 mcg/kg IV Infusion 1.0 mcg/kg/min if Eptifibatide 180 mcg/kg IV Infusion 1.0 mcg/kg/min if Cr Cl <<50 ml/min Cr Cl 50 ml/min Tirofiban 36 IV infusion 0.4 mcg/kg/min IV infusion 0.05 mcg/kg/min if if Tirofiban IV infusion 0.4 mcg/kg/min IV infusion 0.05 mcg/kg/min for 30 mins for 30 mins Cr Cl <30 ml/min Cr Cl <30 ml/min* * Modifiedfrom ACC/AHA 2007 Guidelines for the Management of Patients with UA/NSTEMI. Modified from ACC/AHA 2007 Guidelines for the Management of Patients with UA/NSTEMI.J J Am CollCardiol 2007; 50:1-157. Am Coll Cardiol 2007; 50:1-157. 9.4 9.4 UA/NSTEMI in Diabetes UA/NSTEMI in Diabetes Diabetics have an mortality following an ACS 94,95. The Diabetics have an increased mortality following an ACS 94,95. The 35 glucose level at admission has been shown to be aasignificant glucose level at admission has been shown to be significant
    • Fondaparinux Avoid if Cr Cl < 30 ml/min Avoid if Cr Cl <mcg/kg/min if Eptifibatide 180 mcg/kg IV Infusion 1.0 30 ml/min Clinical mcg/kg Eptifibatide 180 Practice Guidelines ml/min IV Infusion on mcg/kg/min if Cr Cl < 50 1.0 Tirofiban IV infusion 0.4 mcg/kg/min Cr infusion ml/minST management of Unstable Angina/Non mcg/kg/min if IV Cl < 50 0.05 Tirofiban IV infusion 0.4 mcg/kg/min IV infusionml/min for 30 mins Infarction Cr Cl <30 0.05 mcg/kg/min if Elevation Myocardialfor 30 mins (UA/NSTEMI) 2011 Cr Cl <30 ml/min * Modified from ACC/AHA 2007 Guidelines for the Management of Patients with UA/NSTEMI. * Am Coll Cardiol 2007; 50:1-157. J Modified from ACC/AHA 2007 Guidelines for the Management of Patients with UA/NSTEMI. J Am Coll Cardiol 2007; 50:1-157. 9.4 UA/NSTEMI in Diabetes 9.4 UA/NSTEMI in Diabetes Diabetics have an increased mortality following an ACS 94,95. The Diabetics have an increased mortality shown an ACS 94,95. The glucose level at admission has been followingto be a significant glucose level yearadmission with abeen shown to equivalent to LV predictor of 1 at mortality has predictive value be a significant predictor of 1 year mortality with a predictive value equivalent to LV systolic dysfunction 96,97. systolic dysfunction 96,97. Diabetics should be treated aggressively with: Diabetics should be treated aggressively with: Antiplatelet agent – aspirin and clopidogrel or prasugrel. I, B Antiplatelet agent – found and more effective in diabetics Prasugrel has been aspirinto be clopidogrel or prasugrel. 31. 31 I, BIIb, B GP IIb/IIIa inhibitors – a to be more effective in diabetics . a Prasugrel has been found contemporary trial indicated onlyIIb, B GP IIb/IIIa inhibitors – a contemporary trial indicated only a 98,99 modest reduction in adverse events 98,99. I, A modest reduction in adverse events . Early invasive approach – diabetics are however at higher risk I, A – diabetics are however at higher risk Early invasive approachthan non diabetics. of contrast nephropathy of contrast nephropathy than non diabetics. There is still a lack of consensus on the optimal management of blood sugars a lack of consensus on the optimal management of There is still during the acute event. Intensive insulin therapy to achieve normoglycemia inacute event. Intensive not been shown to blood sugars during the the acute setting has insulin therapy to reduce mortality and is associated with an increase in the shown to achieve normoglycemia in the acute setting has not been episodesI, B of hypoglycemia100. A general consensus increase in blood sugars reduce mortality and is associated with an is to keep the episodesI, B of hypoglycemia100.in the acute setting and to keep blood optimal less than 8mmol/l A general consensus is then aim for sugars control following discharge.acute setting and then aim for optimal less than 8mmol/l in the control following discharge. 10. Post Hospital Discharge 10. Post Hospital Discharge The acute phase of UA/NSTEMI is usually 1 to 3 months. The The acute phase of of ischaemic is usually STEMI months. The risk of recurrence UA/NSTEMI events, 1 to 3 or death is risk of during this period. Following this, most patientsdeath is highest recurrence of ischaemic events, STEMI or assume highest during this period. Following this, most patients assume a clinical course similar to that of patients with chronic stable a clinical course similar to that of patients with chronic stable angina. angina. lifestyle modification measures and drug therapies have Several Several lifestyle modification measures and drug therapies have been shown to be effective in improving long-term outcome. been shown to be effective in improving long-term outcome. However they are underutilized. Therefore health care providers 37 should ensure that patients 37 with UA/NSTEMI receive appropriate treatment post hospital discharge and ensure that patients remain compliant to treatment. Important discharge instructions should include: education on medication Patients given sublingual nitrates should be instructed in its proper and safe use. lifestyle change and CV risk factors modification scheduling of timely follow-up appointment and dates for further investigations referral to a cardiac rehabilitation program where appropriate 10.1 Medications post-discharge (Table1, pg 4) 10.1.1 Antiplatelet agents 36 I, A ASA should be prescribed at 75-150 mg daily unless
    • Patients given sublingual nitrates should be instructed in its Clinical safe use. proper and Practice Guidelines on lifestyle change and CV risk factors modification management of Unstable Angina/Non ST scheduling of timely follow-up appointment and dates for Elevation Myocardial Infarction (UA/NSTEMI) 2011 further investigations referral to a cardiac rehabilitation program where appropriate 10.1 Medications post-discharge (Table1, pg 4) 10.1.1 Antiplatelet agentsI, A ASA should be prescribed at 75-150 mg daily unless contraindicated 26,27.I, A In patients who cannot tolerate ASA, clopidogrel is an alternative. It has better risk reduction 101. When clopidopgrel is not available, ticlopidine can be given. The combination of ASA and clopidogrel 75 mg daily should beI, A continued for at least one month and ideally up to 9 to 12 months after UA/NSTEMI treated medically 71,102 and in patients who have undergone PCI with bare metal stents.I, A If patients received drug eluting stents during PCI then dual antiplatelet treatment is recommended 71,102,103. The duration of dual antiplatelet therapy following DESI, C implantation is for 6 to 12 months or longer 103. There are no recent clinical trial data on the use of triflusal in ACS. 10.1.2 β-blockers (see section 7.2.4.2)I, B β-blockers should be continued for patients with ischemia unless contraindicated.I, B Long term treatment following UA/NSTEMI may lead to significant mortality reduction104.I, A β-blockers should be continued indefinitely in patients with 38 reduced LV function, with or without symptoms of heart failure105,106. 10.1.3 Lipid Modifying Therapy I, A There is a large body of evidence that early initiation of statin therapy improves outcome regardless of baseline LDL-C levels in patient with ACS 49-51,07-109. I, A More aggressive lipid lowering further lowers cardiovascular event rates 110. Lipid management includes: 37 I, C Assessment of a fasting lipid profile for all patients, within 24
    • Clinical Practice Guidelines patients with β-blockers should be continued indefinitely in on managementfunction, with or without symptoms of heart reduced LV of Unstable Angina/Non ST failure105,106. Elevation Myocardial Infarction (UA/NSTEMI) 2011 10.1.3 Lipid Modifying Therapy I, A There is a large body of evidence that early initiation of statin therapy improves outcome regardless of baseline LDL-C levels in patient with ACS 49-51,07-109. I, A More aggressive lipid lowering further lowers cardiovascular event rates 110. Lipid management includes: I, C Assessment of a fasting lipid profile for all patients, within 24 hours of hospitalization. I, A Statins, in the absence of contra-indications, regardless of baseline LDL-C and diet modifications, should be initiated soon after admission and continue indefinitely to provide life long benefits 111,112. This also applies to patients post PCI. I, A LDL-C level should be targeted <2.0 mmol/L for most patients 111,112 . I, B Patients with low HDL-C may benefit from fibrates or nicotinic acid 113,114. 10.1.4 Angiotensin-converting enzymes inhibitors (ACE-Is) (Table 7, pg 39) I, A ACE-Is have shown long term benefit in all patients with evidence of LV dysfunction (LVEF ≤40%) 115-117 and in patients with diabetes, hypertension or CKD unless contraindicated 1018-120.IIa, A For all other patients ACE-Is should be considered to prevent recurrence of ischaemic events 121-124.IIa, A For patients with reduced LV systolic function, ACE-I should be initiated early, during the course of hospitalization. Agents and doses of proven efficacy are recommended. 39 38
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Table 7: Recommended dosages of ACE-I in UA/NSTEMI Table 7: Recommended dosages of ACE-I in UA/NSTEMI Table 7: Recommended dosages of ACE-I in UA/NSTEMI Type Type Initiation dose Initiation dose Target dose Target dose Type Initiation dose Target dose Captopril 6.25 mg bd-tds 25-50 mg tds Captopril 6.25 mg bd-tds 25-50 mg tds Captopril 6.25 mg bd-tds 25-50 mg tds Ramipril 2.5 mg bd 10 mg od Ramipril 2.5 mg bd 10 mg od Ramipril 2.5 mg bd 10 mg od Enalapril Enalapril 2.5-5 mg od 2.5-5 mg od 20 mg bd 20 mg bd Enalapril 2.5-5 mg od 20 mg bd Enalapril 2.5-5 mg od 20 mg bd Lisinopril Lisinopril 5 mg od 5 mg od 40 mg od 40 mg od Lisinopril 5 mg od 40 mg od Lisinopril 5 mg od 40 mg od Perindopril Perindopril 2-2.5 mg od 2-2.5 mg od 8-10 mg od 8-10 mg od Perindopril 2-2.5 mg od 8-10 mg od Perindopril 2-2.5 mg od 8-10 mg od 10.1.5 Angiotensin-Receptor Blockers (ARBs) (Table 8, pg 39) 10.1.5 Angiotensin-Receptor Blockers (ARBs) (Table 8, pg 39) 10.1.5 Angiotensin-Receptor Blockers (ARBs) (Table 8, pg 39) 10.1.5 Angiotensin-Receptor Blockers (ARBs) (Table 8, pg 39)I, A ARBs should be substituted for patients with ACE-II, A ARBs should be substituted for patients with ACE-II, A intolerance 125-127. be substituted for patients with ACE-I ARBs shouldI, A intolerance 125-127. be substituted for patients with ACE-I ARBs should125-127 intolerance 125-127. intolerance . Table 8: Recommended dosages of ARB in UA/NSTEMI Table 8: Recommended dosages of ARB in UA/NSTEMI Table 8: Recommended dosages of ARB in UA/NSTEMI Table 8: Recommended dosages of ARB in UA/NSTEMI Type Initiation dose Target dose Type Type Initiation dose Initiation dose Target dose Target dose Type Valsartan Initiation dose 40-80 mg od Target dose 160 mg od Valsartan Valsartan 40-80 mg od 40-80 mg od 160 mg od 160 mg od Valsartan 40-80 mg od 10.1.6 Aldosterone receptor antagonist 160 mg od 10.1.6 Aldosterone receptor antagonist 10.1.6 Aldosterone receptor antagonist 10.1.6 Aldosterone receptor antagonist Long-term aldosterone receptor blockade should be consideredI, B Long-term aldosterone receptor blockade should betreated withI, B in patients aldosterone receptor blockade should be considered Long-term who are in heart failure and already consideredI, B Long-term aldosterone receptor blockade should betreated with considered in patients β-blockers.in heartagents include spironolactone withI, B in patients who are in heart failure and already treated and ACE-I and who are These failure and already in patients β-blockers.in heartagents include spironolactone with 128,129are who failure and already treated ACE-I and β-blockers. These agents include spironolactone and ACE-I and 128,129. epleronone These and ACE-I and β-blockers. These agents include spironolactone and epleronone . epleronone 128,129. 128,129 Care should be .taken in patients with renal dysfunction and epleronone Care should be taken in patients with renal dysfunction and hyperkalaemia. taken in patients with renal dysfunction and Care should be Care should be taken in patients with renal dysfunction and hyperkalaemia. hyperkalaemia. 10.1.7 hyperkalaemia. Anti Anginal Therapy 10.1.7 Anti Anginal Therapy 10.1.7 Anti Anginal Therapy 10.1.7 Anti Anginal Therapy required for patients with successful I, C Anti anginals are not I, C revascularization and no required ischaemia. Anti anginals are not required for patients with successful Anti anginals are not residual for patients with successful I, C revascularization and no required ischaemia. Anti anginals are not for patients with successful I, C revascularization and no residual ischaemia. 10.2 revascularization and no residual ischaemia. Follow-up investigations (Fig 1, pg 5) residual 10.2 Follow-up investigations (Fig 1, pg 5) 5) 10.2 Follow-up investigations (Fig 1, pg UA/NSTEMI patients, the In the Follow-up investigations (Fig 1, pg 5) 10.2 outpatient evaluation of low risk following investigations maybe of low risk UA/NSTEMI patients, the In the outpatient evaluation considered: In the outpatient evaluation of low risk UA/NSTEMI patients, the In the outpatient evaluation of low risk UA/NSTEMI patients, the following investigations maybe considered: following investigations maybe considered: Echocardiogram to assess LV function following investigations maybe considered: Echocardiogram test Treadmill stress Echocardiogram to assess LV function to assess LV function Stress echocardiogram – treadmill or pharmacological stress Echocardiogram test Treadmill stress to assess LV function Treadmill stress test Nuclear perfusion study – treadmill or pharmacological stress Treadmill stress test Stress echocardiogram Stress echocardiogram – treadmill or pharmacological stress MRI – stress MRI for ischaemia and perfusion MRI for viability Stress echocardiogram – treadmill or pharmacological stress Nuclear perfusion study Nuclear perfusion study 40 MRI – stress MRI for ischaemia and perfusion MRI for viability Nuclear perfusion study MRI – stress MRI for ischaemia and perfusion MRI for viability MRI – stress MRI for ischaemia and perfusion MRI for viability 40 40 39 40
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Low risk patients with significant demonstrable ischaemia and allLow risk patients with significant demonstrable ischaemia and allLow risk patients with significant be considered for revascularization.intermediate/high risk patients should demonstrable ischaemia and allintermediate/high risk patients should be considered for revascularization.intermediate/high risk patients should be considered for revascularization. Key messages Key messages Key messages Patients should be on optimal medical therapy at discharge. This Patients should be on optimal medical therapy at discharge. This Patients should , clopidogrel (for at least a monthdischarge. This be on optimal medical therapy at includes ASA I,A, clopidogrel (for at least a month and ideally for includes ASA I,A,I,B includesa year) I,B, β-blockers I,B at CCBsa month and or ARBfor ASA I,A clopidogrel (for + least I,C, ACE-I I,A ideally for and ideally I,B at least at least a year) I,B, β-blockers I,B + CCBs I,C, ACE-I I,A or ARB I,B at least a year) , β-blockers I,B + CCBs I,C, ACE-I I,A or ARB I,B and statins I,A. (Table 1, pg 4) I,A and statins I,A. (Table 1, pg 4) and statins . (Table 1, pg 4) These drugs should be uptitrated during outpatient visits to the These drugs should be uptitrated during outpatient visits to the These drugs should be doses I,C. during outpatient visits to the uptitrated recommended tolerated doses I,C. recommended tolerated recommended tolerated doses I,C. Low risk patients should be assessed non-invasively for Low risk patients should be assessed non-invasively for Low risk I,C. (Fig 1, pg 5) patients should be assessed non-invasively for ischaemia I,C ischaemia I,C. (Fig 1, pg 5) ischaemia . (Fig 1, pg 5)11. Cardiac Rehabilitation/Secondary prevention11. Cardiac Rehabilitation/Secondary preventionCardiac rehabilitation is aimed at improving the physical and psychologicalwell being of the patient. It at improving the physical and psychologicalCardiac rehabilitation is aimed has been shown to reduce mortality bywell being of 20%-25% 130-132.has been shown to reduce mortality byapproximately the patient. It There was also a trend towards reduction 130-132approximately 20%-25%over a .median was also a trend towards .in non-fatal recurrent MI There follow-up of 12 months 133reductionin non-fatal recurrent MI over a median follow-up of 12 months 133.11.1 Cardiac rehabilitation programs include:11.1 Cardiac rehabilitation programs include: Counselling and educating the patient and family members on CAD Counselling and educating the patient and family members on CAD Beginning an exercise program Beginning an exercise program factors such as high blood pressure, Helping the patient modify risk smoking, high blood cholesterol, physical as high blood pressure, Helping the patient modify risk factors such inactivity, obesity and smoking, high blood cholesterol, physical inactivity, obesity and diabetes diabetes vocational guidance to enable the patient to return to work Providing Providing vocational guidance to enable the patient to return to work Supplying information on physical limitations Supplying information on physical limitations Supplying information on physical limitations Educating and ensuring compliance to medications Educating and ensuring compliance to medications Educatingemotional support Providing and ensuring compliance to medications Providing emotional support Providing emotional supportCardiac rehabilitation/secondary prevention programs are generallyCardiac rehabilitation/secondary prevention programs are generallyCardiac rehabilitation/secondary prevention programs are generallydivided into 3 main phases:divided into 3 main phases:divided into 3 main phases: Phase 1: Inpatient CR (also known as Phase 1 CR): a program that Phase 1: Inpatient CR (also known as Phase 1 CR): a program that Phase 1: Inpatient CR (also known as Phase to CR): a program that delivers preventive and rehabilitative services 1 hospitalized patients delivers preventive and rehabilitative services to hospitalized patients delivers preventive and rehabilitative services to hospitalized patients following ACS following ACS following ACS Phase 2: Early outpatient CR (also known as Phase 2 CR): generally Phase 2: Early outpatient CR (also known as Phase 2 CR): generally within 2: first to 6 months but continuing up to 1 year Phasethe Early3outpatient CR (also known as Phase 2 CR): generally within the first 3 to 6 months but continuing up to 1 year within the first 3 to 6 months but continuing up to 1 year Phase 3: Long-term outpatient CR (also known as Phase 3 or Phase 41 4 CR): beyond 1 year 41 4111.2 Return to physical activity 40
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) or Phase Phase 3: Long-term outpatient CR (also known as Phase 3 2011 4 CR): beyond 1 year11.2 Return to physical activityPhysical activity can be resumed at 50% of maximal exercise capacity in apatient with preserved LV function without inducible ischemia within 1week post-discharge. This should be gradually increased over timepreferably guided by treadmill stress test.11.3 Risk factor modification: Smoking cessation – Patients who quit smoking can reduce the rate of reinfarction and death as early as 1 year. Weight – Achieve or maintain optimal body weight. Exercise – Encourage a minimum of 30–60 minutes of moderate activity 3-4 times weekly (walking, cycling, swimming or other equivalent aerobic activities). Diet – To consume low cholesterol or low saturated fat diet. Lipids – Aim for an LDL-C < 2.0 mmol/l. Hypertension – Aim for a blood pressure of <140/85 mmHg. In diabetics the target is <130/80 mmHg. In elderly patients, a higher BP target may be acceptable. Diabetes Mellitus – Optimal glycemic control in diabetes. (Refer CPG on Diabetes)11.4 Discharge Instructions Therapeutic lifestyle changes should be initiated in all patients and reemphasized during follow up. Patients should be on optimal medical therapy. (Table 1, pg 4). They should be educated on the importance of adherence to drug therapy to ensure optimal outcomes. Patients with DES should be warned of the consequences of non compliance to anti platelet drug therapy. The doses of ACE-I/ARB and β-blockers should be uptitrated to the maximal tolerated doses. Patients should be instructed on how to use GTN. If the chest pain does not subside after 2 GTN’s or if there is a change in the usual pattern of angina, they should go to the nearest health facility. 42 41
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    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011121. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double blind, placebo- controlled, multicentre trial (the EUROPA study). Lancet 2003; 362 : 782-788122. Yusuf S, Sleight P, Pogue J et al. Effects on an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342 : 145-153123. Dagenais 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 : 581-588124. Danchin N, Cucherat M, Thuillez C et al. Angiotensin-converting-enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials. Arch Intern Med 2006; 166 : 787-796125. Fox K, Ferrari R, Yusuf S, Borer JS. Should angiotensin-converting-enzyme- inhibitors be used to improved outcome in patients with coronary artery disease and ‘preserved’ left ventricular function? Eur Heart J 2006; 27 : 2154-2157126. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction-may they rest in PEACE? N Engl J Med 2004; 351: 2115-7127. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antogonist Losartan. Lancet 2002; 360 : 752-760128. Pfeffer MA, McMurray JJ, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349 : 1893-1906129. Effect of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial: The Telmisartan Randomized Assessment Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Lancet 2008; 372 : 1174-1183.130. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709-717131. Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348 : 1309-1321132. Oldridge NB, Guyatt GH, Fischer ME, Rimm AA. Cardiac rehabilitation after myocardial infarctionCombined experience of randomized clinical trials. JAMA 1988; 260 : 945-950.133. OConnor GT, Buring JE, Yusuf S, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989; 80 : 234- 244.134. McAlister FA, Lawson FM, Teo KK, Armstrong PW. Randomised trials of secondary prevention programmes in coronary heart disease: systematic review Br Med J 2001; 323 : 957-962135. Clark AM, Hartling L, Vandermeer B, McAlister FA. Meta-analysis: secondary prevention programs for patients with coronary artery disease Ann Intern Med 2005; 143 : 659-672 52 50
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 APPENDIX I: Braunwald’s Classification of Unstable Angina* CLINICAL CIRCUMSTANCES A B CSeverity Develops in Develops in Develops Presence of Absence of Within 2 weeks Extracardiac Extracardiac of MI Condition That Condition (Primary (Postinfarction Intensifies UA) UA) Myocardial Ischemia (Secondary UA)I—New onset ofsevere angina oraccelerated IA IB ICangina; no restpainII—Angina at restwithin past monthbut not withinpreceding 48 hours IIA IIB IIC(angina at rest,subacute)III—Angina at restwithin 48 hours(angina at rest, IIIA IIIB-Tneg IIIB-Tpos IIICacute)UA : Unstable angina; T : Troponins*Hamm CW, Braunwald E. A classification of unstable angina revisited. Circulation.2000 ;102 :118-22. 53 51
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 Appendix II:II: Elevationsof cardiac troponin inin the absence of Appendix Elevations of cardiac troponin the absence of overt ischaemicheart disease* overt ischaemic heart disease*Damage related to to secondarymyocardial ischaemia (MI type 2) 2) Damage related secondary myocardial ischaemia (MI type Tachy- or bradyarrhythmias Tachy- or bradyarrhythmias Aortic dissection and severe aortic valve disease Aortic dissection and severe aortic valve disease Hypo- or hypertension, e.g. haemorrhagic shock, hypertensive emergency Hypo- or hypertension, e.g. haemorrhagic shock, hypertensive emergency Acute and chronic heart failure without significant concomitant coronary artery Acute and chronic heart failure without significant concomitant coronary artery disease (CAD) disease (CAD) cardiomyopathy Hypertrophic Hypertrophicvasculitis, e.g. systemic lupus erythematosus, Kawasaki syndrome Coronary cardiomyopathy Coronary vasculitis, e.g. systemic withouterythematosus, Kawasaki syndrome Coronary endothelial dysfunction lupus significant CAD, e.g. cocaine abuse Coronary endothelial dysfunction without significant CAD, e.g. cocaine abuse Damage not related to myocardial ischaemiaDamage not related to myocardial ischaemia Cardiac contusion Cardiac contusion with surgery Cardiac incisions Cardiac incisions with surgery therapy Radiofrequency or cryoablation Rhabdomyolysis with cardiac involvement Radiofrequency or cryoablation therapy Myocarditis Rhabdomyolysis with cardiac involvement Cardiotoxic agents, e.g. anthracyclines, herceptin, carbon monoxide poisoning Myocarditis Severe burns affecting >30% of body surface Cardiotoxic agents, e.g. anthracyclines, herceptin, carbon monoxide poisoning Severe burns affecting >30% of groupsurface Indeterminant or multifactorial bodyIndeterminant or multifactorial group Apical ballooning syndrome Severe pulmonary embolism or pulmonary hypertension Apical ballooning syndrome Peripartum cardiomyopathy Severe pulmonary embolism or pulmonary hypertension Renal failure Peripartumacute neurological diseases, e.g. stroke, trauma Severe cardiomyopathy Renal failure diseases, e.g. amyloidosis, sarcoidosis Infiltrative Extreme exertion Severe acute neurological diseases, e.g. stroke, trauma Sepsis Infiltrative diseases, e.g. amyloidosis, sarcoidosis Extreme exertion failure Acute respiratory Frequent defibrillator shocks Sepsis Acute respiratory failure Frequent defibrillator shocksal for Study Group on Biomarkers in Cardiology of the ESC *Thygesen K, Mair J,Katus H et Working Group on Acute Cardiac Care. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010; 31 : 2197-2204. 54*Thygesen K, Mair J,Katus H et al for Study Group on Biomarkers in Cardiology of the ESCWorking Group on Acute Cardiac Care. Recommendations for the use of cardiac troponinmeasurement in acute cardiac care. Eur Heart J 2010; 31 : 2197-2204. 54 52
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011Appendix III: Likelihood That Signs and Symptoms Represent an ACS Appendix III: Likelihood That Symptoms Represent an ACS secondary to CAD secondary CADGreater Likelihood Greater Likelihood Lower Likelihood Lower LikelihoodHistory HistoryChest or left arm pain or discomfort as Chest or left arm pain or discomfort Chest pains in the absence of Chest pains in the absence ofchief symptom reproducing prior chief symptom reproducing prior any of the greater likelihood any of the greater likelihooddocumented angina documented angina characteristics characteristicsKnown history of CAD, including MI Known history of CAD, including Recent cocaine use Recent cocaine useNew chest or left arm pain or discomfort New chest or left arm pain oras chief symptom as chief symptomAge greater than 70 years Age greater than 70 yearsMale sex Male sexDiabetes mellitus Diabetes mellitusExamination ExaminationTransient MR murmur, hypotension, Transient MR murmur, hypotension, Chest discomfort reproduced Chest discomfort reproduceddiaphoresis, pulmonary edema, or rales diaphoresis, pulmonary edema, by palpation by palpationExtracardiac vascular disease Extracardiac vascular diseaseECG ECGNew, or presumably new, transient ST- New, or presumably new, transient T-wave flattening or inversion T-wave flattening or inversionsegment deviation (1 mm or greater) or T- less than 1 mm in leads with segment deviation (1 mm or greater) less than 1 mm in leads withwave inversion in multiple pre-cordial wave inversion in multiple pre-cordial dominant R waves dominant R wavesleads leads Normal ECG Normal ECGCardiac Biomarkers Cardiac BiomarkersElevated cardiac TnI, TnT, or CK-MB Elevated cardiac TnI, TnT, or Normal Normalmarkers markersModified from Braunwald E, et al. Unstable Angina: Diagnosis and Management. 1994;3-1- Modified from Braunwald E, et al. Unstable Diagnosis and Management. 1994;3-1-AHCPR Publication No 94-0602:1-154. AHCPR Publication No 94-0602:1-154. 55 55 53
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 APPENDIX IV : TIMI RISK SCORE FOR UA/NSTEMI APPENDIX IV : TIMI RISK SCORE FOR UA/NSTEMITIMI Risk Score All-Cause Mortality, New or Recurrent TIMI Risk Score All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia MI, or Severe Recurrent Ischemia Requiring Urgent Revascularization Requiring Urgent Revascularization Through 14 d After Randomization, % Through 14 d After Randomization, % 0-1 4.7 0-1 4.7 2 8.3 2 8.3 3 13.2 3 13.2 4 19.9 4 19.9 5 26.2 5 26.2 6-7 40.9 6-7 40.9The TIMI risk score is determined by the sum of the presence of 7 variables at The TIMI risk score is determined by the sum of the presence of 7 variables atadmission: admission:1 point is given for each of the following variables: 1 point is given for each of the following variables: Age 65 y or older At least 3 65 y factors for CAD ( family history of premature CAD, Age risk or older hypertension,elevated cholesterols,(active smoker,of premature CAD, At least 3 risk factors for CAD family history diabetes) hypertension,elevated cholesterols, active smoker, diabetes) Known CAD (coronary stenosis of > 50%) Known CAD (coronary stenosis of > 50%) Use of aspirin in prior 7 days ST-segmentaspirin in prior 7 days ECG Use of deviation (>0.5mm) on At least 2 anginal episodes in prior 24 on ECG ST-segment deviation (>0.5mm) h Elevated serum cardiac biomarkersprior 24 h At least 2 anginal episodes in Elevated serum cardiac biomarkersTotal Score = 7 points Total Score = 7 pointsLow Risk : < 2 pointModerate Risk :3-4 points Low Risk: < 2 pointHighModerate Risk: 3-4 points Risk : >5 points High Risk : >5 pointsAdapted from : Adapted from : Cohen M, Bernink PJ, et al. The TIMI risk score for unstable Antman EM, angina/non-ST EM, Cohen M,method forPJ, et al. The and therapeutic decision Antman elevation MI: a Bernink prognostication TIMI risk score for unstable making. JAMA 2000; 284 : 835–42 a method for prognostication and therapeutic decision angina/non-ST elevation MI: . Sabatine MS,JAMA 2000; 284Giugliano . RP, et al. Implications of upstream making. Morrow DA, : 835–42 glycoprotein IIb/IIIa inhibition DA, Giugliano RP, et stenting in the invasive Sabatine MS, Morrow and coronary artery al. Implications of upstream management of unstable inhibition and coronary artery stenting in the invasive glycoprotein IIb/IIIa angina/non ST elevation myocardial infarction. A comparison of the Thrombolysis in Myocardial ST elevation myocardial and the management of unstable angina/non Infarction (TIMI) IIIB trial infarction. A Treat comparison of the Thrombolysis in Myocardial Infarction (TIMI) Invasive or the angina with Aggrastat and determine Cost of Therapy with IIIB trial and Conservative Strategy (TACTICS)-TIMI 18determine Cost of Therapy 874-880. Treat angina with Aggrastat and trial. Circulation 2004; 109 : with Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial. Circulation 2004; 109 : 874-880. 56 56 54
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011APPENDIX V: V: GRACE PREDICTION SCORE CARD AND NOMOGRAM APPENDIX GRACE PREDICTION SCORE CARD AND NOMOGRAM FOR ALL CAUSE MORTALITY FROM DISCHARGE TO 6 TO 6 FOR ALL CAUSE MORTALITY FROM DISCHARGE MONTHS* MONTHS**Eagle KA,Lim MJ,Dabbous OH et al for the Grace Investigators. A Validated Prediction Model for AllForms of Acute Coronary Syndrome.Estimating the Risk of 6-Month Postdischarge Death in anInternational Registry JAMA. 2004;291:2727-2733. *Eagle KA,Lim MJ,Dabbous OH et al for the Grace Investigators. A Validated Prediction Model for Forms of Acute Coronary Syndrome.Estimating the Risk of 6-Month Postdischarge Death in an 57 International Registry JAMA. 2004;291:2727-2733. 57 55
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 APPENDIX VI: VI: Calculation Of Creatinine Clearance APPENDIX Calculation Of Creatinine Clearance APPENDIX VI: Calculation Of Creatinine Clearance APPENDIX VI: Calculation Of Creatinine Clearance Estimated GFR (ml/min) = (140-age) x weight Estimated GFR (ml/min) = (140-age) x weight or or (140-age) 1.2 1.2 (140-age)Estimated Estimated GFR (ml/min) = (140-age) x weight1.2 (140-age) (140-age) GFR (ml/min) = (140-age) x weight or or 1.2 (0.814 x SCr [µmol/L ]) ]) (0.814 x SCr [µmol/L SCr [µmol/L ] SCr [µmol/L ] (0.814 x S(0.814 x SCr [µmol/LSCr [µmol/L Cr [µmol/L ] Cr [µmol/L ]) ]) S] SCr : SCr : serum creatinine serum creatinineSCr : serum creatinine creatinine SCr : serum For women multiply by 0.850.85 For women multiply byFor women multiply by 0.85 by 0.85 For women multiply Severity Of CKD* Severity Of CKD* Severity Of CKD* Of CKD* Severity SEVERITY OF CKD SEVERITY OF CKD CREATININE CLEARANCE CREATININE CLEARANCESEVERITY OF CKD OF CKD SEVERITY CREATININE CLEARANCE CREATININE CLEARANCE Normal to mild mild Normal to >60 >60 ml/min ml/minNormal toNormal to mild mild >60 ml/min >60 ml/min Moderate Moderate 30-59 ml/min 30-59 ml/minModerate Moderate 30-59 ml/min30-59 ml/min SevereSevere <30 <30 ml/min ml/minSevere Severe <30 ml/min <30 ml/min * National Kidney Foundation. K/DOQI clinical practice guidelines for chronic * National Kidney Foundation. K/DOQI clinical practice guidelines for chronic* kidney disease: Foundation. K/DOQI clinical and clinicalstratification. Am Kidney chronic National *Kidney evaluation, classification, practice guidelines guidelines Kidney kidney National Kidney Foundation. K/DOQI and disease: evaluation, classification, stratification. Am Jchronicfor practice for JkidneyDis.2002; 39evaluation,S1–S226 Dis.2002;kidney disease: evaluation, classification, and stratification. Am J Kidney disease: (suppl 1): classification, and stratification. Am J Kidney 39 (suppl 1): S1–S226Dis.2002; 39 (suppl 1): S1–S226 S1–S226 Dis.2002; 39 (suppl 1): APPENDIX VII: Prevention of Contrast Induced Nephropathy APPENDIX VII: Prevention of Contrast Induced Nephropathy APPENDIX VII: Prevention of Contrast Induced Nephropathy APPENDIX VII: Prevention of Contrast Induced Nephropathy ACC/ESC ACC/ESC Classification Classification ACC/ESCACC/ESC ClassificationClassification Contrast Agent Contrast Agent - Isomolar agent Agent - Isomolar agent Contrast Agent Contrast I, A I, A - Isomolar -agent agents - Low Low Isomolar agents - osmolar osmolar agent IIa, B B I, A I, A IIa, - Low - use Lowvolume agents - use minimalagents - minimal volume osmolar osmolar IIa, I, C I, C B B IIa, - use minimal volume volume - use minimal I, C I, C Avoid nephrotoxic agents eg eg Avoid nephrotoxic agents I, C I, C NSAIDS,metforminagents egagents eg NSAIDS,metformin Avoid nephrotoxic Avoid nephrotoxic I, C I, C NSAIDS,metformin NSAIDS,metformin Saline Infusion Saline Infusion I, C I, C Saline Infusion Infusion Saline I, C I, C Sodium Bicarbonate Sodium Bicarbonate IIa, B B IIa, Sodium Bicarbonate Sodium Bicarbonate IIa, B IIa, B Acetylcysteine Acetylcysteine IIb, B B IIb, Acetylcysteine Acetylcysteine IIb, B IIb, B 58 58 58 58 56
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011 APPENDIX VIII: Prevention ofof Contrast Induced Nephropathy APPENDIX VIII: Prevention Contrast Induced Nephropathy AGENT AGENT CONCENTRATION DOSE / FLOW RATE CONCENTRATION DOSE / FLOW RATE Sodium Chloride* 0.9% solution Sodium Chloride* 0.9% solution Rate ofof 1.0-1.5 ml/kg/hrfor Rate 1.0-1.5 ml/kg/hr for 3h-12h before and 6h-24h 3h-12h before and 6h-24h after the procedure ensuring after the procedure ensuring a a urine flow rate of 150 urine flow rate of 150 ml/hour ml/hour Reduce rate to 0.5 ml/kg/hr ifif Reduce rate to 0.5 ml/kg/hr LVEF<40% LVEF<40% Sodium 154 mEq/L in 5% 3 ml/kg/hr for 1 hour before Sodium 154 mEq/L in 5% 3 ml/kg/hr for 1 hour before Bicarbonate** dextrose in water the contrast followed by an Bicarbonate** dextrose in water the contrast followed by an (154 ml of infusion of 1 ml/kg/hr for 6 (154 mlmEq/l of 1000 of infusionafter the procedure hours of 1 ml/kg/hr for 6 1000 mEq/l of sodium bicarbonate hours after the procedure sodium bicarbonate + 850 ml of 5% + 850 ml of 5% Dextrose) Dextrose) N- 1200 mg twice daily, one day N-acetylcysteine*** 1200 mgand one day one day before twice daily, after the acetylcysteine*** before and one day after the contrast contrast * McCullough PA, Bertrand ME, Brinker JA, Stacul F. A meta-analysis of the renal safety of* McCulloughiodixanol comparedBrinkerlow-osmolar F. A meta-analysis of the renal safety 48: isosmolar PA, Bertrand ME, with JA, Stacul contrast media. J Am Coll Cardiol. of 2006; 692–9.isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol. 48:2006; 692–9. ** Briguori C, Colombo A, Violante A et al. Standard vs double dose of N-acetylcysteine to** Briguori contrast agent associated nephrotoxicity. Eur Heart J 2004; 25 N-acetylcysteine to prevent C, Colombo A, Violante A et al. Standard vs double dose of : 206-211.prevent contrast agent associated nephrotoxicity. Eur Heart J 2004; 25 : 206-211. *** Tepel M, Van der Giet M, Schwarzfeld C et al. Prevention of radiographic-contrast-*** agent-induced reductions M, renal functionC etacetylcysteine. N Engl J Med. 2000; 343: Tepel M, Van der Giet in Schwarzfeld by al. Prevention of radiographic-contrast- 180–184.agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000; 343:180–184. 59 59 57
    • Clinical Practice Guidelines on management of Unstable Angina/Non ST Elevation Myocardial Infarction (UA/NSTEMI) 2011ACKNOWLEDGMENTSACKNOWLEDGMENTSThe committee of this guideline would like to express their gratitude andThe committee the this guidelinetheir contribution:appreciation to of following for would like to express their gratitude andappreciation to the following for their contribution: Technical Advisory Committee, Clinical Practice Guidelines, Ministry of Technical Advisory Committee, Clinical Practice Guidelines, Ministry of Health for their valuable input and feedback Healthof external reviewers who reviewed the draft Panel for their valuable input and feedback Panel of external reviewers who reviewed the draft Secretarial assistance from sanofi-aventis Secretarial assistance from sanofi-aventisDISCLOSURE STATEMENTDISCLOSURE STATEMENTThe panel members have no potential conflict of interest to disclose.The panel members have no potential conflict of interest to disclose.SOURCES OF FUNDINGSOURCES OF FUNDINGThis CPG was made possible by an unrestricted educational grant fromThis CPG was (M) Sdn Bhd.Sanofi-Aventis made possible by an unrestricted educational grant from The funding body did not influence theSanofi-Aventis guideline. Bhd.content of this (M) Sdn The funding body did not influence thecontent of this guideline. 60 60 58
    • Clinical Practice Guidelines on management of Unstable Angina/Non STElevation Myocardial Infarction (UA/NSTEMI) 2011 59