1. ACUTE CORONARY SYNDROMES R MAHARAJ EMERGENCY MEDICINE

2. LECTURE OUTLINE INTRODUCTION – EPIDEMIOLOGY/PREVALENCE/DEFINITION PATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROMES APPROACH TO SUSPECTED ACUTE CORONARY SYNDROME – GUIDELINE UPDATE TREATMENT/MANAGEMENT UPDATE

3. INTRODUCTION Coronary Artery Disease – leading cause of morbidity & mortality in industrialised nations. Although decrease in cardiovascular mortality  still major cause of morbidity & burden of disease. South African perspective of cardiovascular disease: “A World in One Country” - Yusuf et al Epidemiological transitions of cardiovascular disease.

4. HIGH RISK POPULATION FOR CAD/ACS: INDIAN/WHITE/COLOURED INCREASING rate in Black population – lifestyle/socioeconomic changes, urbanisation GF Jooste stats: 23.8% of admissions to resus. unit for chest pain/acs related (stats 1Jan 2009 – 28 Feb 2009) 150/628 entries. In US – 2004 – 1.56 million admissions for ACS – 669 000 for unstable angina, 896 000 for MI Higher prevelance for NSTEMI.

5. DEFINITIONS CAD is a continuum of disease…. Angina -> unstable angina -> AMI -> sudden cardiac death Acute coronary syndrome encompasses unstable angina, NSTEMI, STEMI Stable angina – transient episodic chest pain d/t myocardial ischaemia, reproducible, frequency constant over time.usually relieved with rest/NTG. Classification of angina – Canadian Cardiovascular Society classification.

6. Canadian Cardiovascular Association Classification of Angina CLASS 1 NO PAIN WITH ORDINARY PHYSICAL ACTIVITY CLASS 2 SLIGHT LIMITATION OF PHYSICAL ACTIVITY – PAIN OCCURS WITH WALKING, CLIMBING STAIRS,STRESS CLASS 3 SEVERE LIMITATION OF DAILY ACTIVITY – PAIN OCCURS ON MINIMAL EXERTION CLASS 4 UNABLE TO CONDUCT ANY ACTIVITY WITHOUT PAIN, PAIN AT REST

7. UNSTABLE ANGINA – Pain occurring at rest – duration > 20min, within one week of first visit New onset angina – ~ Class 2 severity, onset with last 2 months Worsening of chest pain – increase by at least 1 class, increases in frequency, duration Angina becoming resistance to drugs that previously gave good control. NB! ECG – normal, ST depression(>0.5mm), T wave changes

8. ACUTE MYOCARDIAL INFARCTION – ECC/ACC DEFN –rise and fall in cardiac enzymes with one or more of the following: Ischaemic type chest pain/symptoms ECG changes – ST changes, pathological Q waves Coronary artery intervention data Pathological findings of an acute MI NSTEMI = UNSTABLE ANGINA SYMPTOMS/FINDINGS + POSITIVE CARDIAC ENZYMES STEMI = ST ELEVATION ON ECG + SYMPTOMS

9. WHY IS IT IMPORTANT TO RECOGNISE PATIENTS WITH UNSTABLE ANGINA?? 5 -17% suffer an MI within a week after admission. 3 -15% die within a year.

10. ACS PATHOPHYSIOLOGY Distruption of coronary artery plaque -> platelet activation/aggregation /activation of coagulation cascade -> endothelial vasoconstriction ->intraluminal thrombus/embolisation -> obstruction -> ACS Severity of coronary vessel obstruction & extent of myocardium involved determines characteristics of clinical presentation

11. APPROACH Identifying those with chest pain suggestive of IHD/ACS. Thorough history required: Character of pain Onset and duration Location and radiation Aggravating and relieving factors Autonomic symptoms TYPICAL VS ATYPICAL HISTORY Failure to recognise symptoms other than chest pain -> approx 2 hr delay in seeking medical attention

12. CHARACTERISTICS OF TYPICAL ANGINAL CHEST PAIN (ADAPTED FROM ROSEN’S, EMERGENCY MEDICINE) CHARACTERISTICSUGGESTIVE OF ANGINALESS SUGGESTIVE OF ANGINA TYPE OF PAINDULL PRESSURE/CRUSHING PAIN SHARP/STABBING DURATION2-5 MIN, <20 MINSECONDSTO HOURS/CONTINUOUS ONSETGRADUALRAPID LOCATION/CHEST WALL TENDERNESS SUBSTERNAL, NOT TENDER TO PALP. LATERAL CHEST WALL/TENDER TO PALP. REPRODUCIBALITYWITH EXERTION/ACTIVITY WITH BREATHING/MOVING AUTONOMIC SYMPTOMSPRESENT USUALLYABSENT

13. ATYPICAL PAIN RISK FACTORS FOR DEVELOPING ATYPICAL PAIN: Diabetes, females, non white patients, elderly, dementia, no prior history of MI ATYPICAL SYMPTOMS: GIT symptoms Syncope SOB Pleuritic/positional pain Chest wall tenderness No chest pain/symptoms NRMI 2 STUDY – MI without chest pain -> increased risk of death (23% vs 9%) More complications – hypotension,heart failure, stroke Delayed ED presentation, delayed intervention

14. RISK STRATIFICATION IN ACS Reasons : Provides prognostic information Determines treatment and level of intervention -> low risk patients – early discharge, high risk -> admission to high care Helps decongest the ED and make available medical resources to more needy patients Risk stratification should be ongoing – at admission, 6-8 hrs, 24hrs, discharge

15. TOOLS USED IN RISK STRATIFICATION HISTORY ECG BIOCHEMICAL MARKERS

17. ECG First point of entry into ACS algorithm Abnormal or normal Neither 100% sensitive or 100% specific for AMI Single ECG for AMI – sensitivity of 60%, specificity 90% Represents single point in time –needs to be read in context Normal ECG does not exclude ACS – 1-6% proven to have AMI, 4% unstable angina

18. GUIDELINES: Initial 12 lead ECG – goal door to ECG time 10min, read by experienced doctor (Class 1 B) If ECG not diagnostic/high suspicion of ACS – serial ECGs initially 15 -30 min intervals (Class 1 B) ECG adjuncts – leads V7 –V9, RV 4 (Class 2a B) Continuous 12 lead ECG monitoring reasonable alternative to serial ECGs (Class 2a B)

19. BIOCHEMICAL MARKERS IDEAL MARKER: High concentration in myocardium Myocardium specific Released early in injury Proportionate to injury Non expensive testing Troponins CKMB Myoglobin Other markers

21. TROPONINS T/I Troponin T vs I – both equivalent in diagnostic and prognostic abilities ( except in renal failure – Trop T less sensitive) Elevation ~ 2hrs to 12hrs ~30 – 40% of ACS patients without ST elevation – had normal CKMB but elevated troponins on presentation Meta-analysis (Heindereich et al) – odds of death increased 3 to 8 fold with positive troponin

22. Mortality at 42 days in troponin positive patients

23. MYOGLOBIN Rapid release within 2 hours Not cardiac specific Rule out for NSTEMI rather than rule in. CKMB Used in conjunction with troponins Useful in diagnosing re-infarction

24. MARKER CHANGE SCORES 2 hour delta CKMB mass Aim – to exclude MI within 6hrs of symptom onset Determine changes in serum marker levels over certain time intervals –delta values Increasing values while still within normal range suggestive of ischaemia – more rapid anti- ischaemic mxn.

25. OTHER MARKERS INDICATORS OF INFLAMMATION OR ACTIVATION OF COAGULATION CASCADE: Myeloperoxidase, soluble CD40 ligand, IL6, hsCRP, d dimer, prothrombin fragment 1 & 2 Elevated before onset of irreversible injury Lack specificity Complex lab assays

27. ISCHAEMIA MODIFIED ALBUMIN Measured with albumin cobalt binding assay In ischaemia -> decreased binding of albumin to cobalt Increased with minutes of ischaemia – elevated for 6-12hrs – gone by 24hrs ~90% negative predictive value Combined with myoglobin/CKMB/troponin – increases diagnostic sensitivity of ischaemia by 40% Possible role for rule criteria in low risk patients Positive IMA – high risk patients – more aggressive mxn Positive in hypoxic disorders – poor specificity in this setting

28. B –type Natriuretic Peptide: released from heart muscle in response to increased ventricular wall stress. Studies – BNP not a specific marker but a strong predictor of ACS especially in patients with chest pain, no ECG changes, non diagnostic troponins. Also positive in heart failure, PE, atrial arrythmias, renal failure Pregnancy Associated Plasma Protein A (PAPP-A): Released when plaque ruptures Predictor of ischaemia

29. HEART FATTY ACID BINDING PROTEIN (HF ABP) Identifies AMI <4hrs after onset Protein involved in myocardial lipid synthesis, but also expressed outside heart Therefore may be sensitive but not specific for injury Possible role in multi-marker strategy IMAGING MODALITIES Cardiac MRI Multidetector CT for coronary calcification Coronary CT angiography Undergoing clinical evaluation

30. 2007 ACC/AHA guidelines: Cardiac biomarkers measured in all patients with suspicion of ACS (Class 1 B) Troponin preferred marker( Class 1 B) If troponin negative within 6 hours of onset, repeat 8-12hours later(Class 1 B) Remeasuring of positive biomarkers to determine infarct size/necrosis (Class 2a B) Patients presenting within 6 hours of symptom onset – myoglobin in conjunction with troponin measured (Class 2b B) 2hr delta CKMB/Delta troponin considered in <6hr presentation (Class 2b B) BNP level – for global risk assessment(Class 2b B) Class 3 – AST/LDH/CK without CKMB

31. RISK STRATIFICATION MODELS

32. TIMI RISK SCORE –increase in mortality with increasing score ~40% all cause mortality at 14 days for patients requiring urgent revascularisation

33. WHICH MODEL IS MOST APPROPRIATE?? 2007 ACS/AHA GUIDELINES: Risk stratification models useful in decision making with regard to treatment options ( Class 2a B) TIMI vs GRACE vs PURSUIT PURSUIT & GRACE risk scores allow better discrimination of in hospital and 1 year mortality in patients compared to TIMI. (Andrew et al, Risk scores for risk stratification in ACS …) What’s appropriate in our setting???

34. MANAGEMENT ALGORITHM

35. MANAGEMENT UPDATE 2007ACS/AHA GUIDELINES: Rapid catergorisation of patient (Class 1 C) Possible ACS, non diagnostic ECG/biomarkers – observed in facility with cardiac monitoring (Class 1 C) Alternative to in patient treatment: for those with 12hr ECG/markers negative – stress ECG in 72hrs (Class 1 C) Giving precautionary treatment for those for OPD stress (Class 1 B)

36. INITIAL INVASIVE VS INITIAL CONSERVATIVE STRATEGY CLASS 1 RECOMMENDATIONS: Early invasive strategy for refractory angina, hemodynamic instability (LOE B) Early invasive strategy for stabilised patients with elevated risk for clinical events. High risk factors include: Recurrent angina, ischaemia at rest or minimal activity Elevated troponins New ST depression Signs of heart failure/worsening mitral regurg. Ventricular tachycardia Prior CABG PCI in last 6 months High TIMI/GRACE scores LVEF < 40%

37. CLASS 2b May opt for initial conservative strategy in stabilised high risk patients – dependent on patient/physician preference (LOE B) CLASS 3 Invasive strategy -not recommended in patients with multiple co morbidities, low risk patients, patients not consenting.(LOE C)

38. UA/NSTEMI – PHARMACOTHERAPY UPDATE GENERAL: IV B Blockers downgraded from Class 1 to 2a recommendation. (COMMIT Trial) Oral B Blockers in first 24hrs still Class 1 – but not used in signs of heart failure, cardiogenic shock and reactive airway disease.(LOE B) MORPHINE downgraded from Class 1 to 2a – findings from CRUSADE Registry

39. NSTEMI- PHARMACOTHERAPY UPDATE ANTIPLATELET THERAPY: CLASS 1 RECOMMENDATION Aspirin to all patients as soon as possible and continued (if no C/I) (LOE A) Initial dose 162 -325mg Maintenance 75 -162mg No added benefit from higher doses except post stenting Clopidogrel for those allergic to aspirin or major GI bleeding (LOE A) For initial invasive strategy – aspirin + clopidogrel or IV glycoprotein 2b/3a therapy (LOE A) Abciximab if no delay in angiography/PCI, eptifibatide/tirofiban if delayed angiography(LOE B)

40. CLASS 2a In patients managed conservatively who develop recurrent ischaemia – on clopidogrel/ASA/Anticoagulant – can add glycoprotein inhibitor. (LOE C) Invasive strategy – can use clopidogrel + glycoprotein inhibitors(LOE C) CLASS 2b In patients managed conservatively – can add glycoprotein inhibitor therapy, in addition to aspirin & anticoagulant (LOE B)

41. CLASS 3 ABCIXIMAB should not be given if PCI not planned (LOE A)

42. For initial conservative strategy: Aspirin + Clopidogrel + anticoagulant – administered for 1 month(LOE A), continued ideally up to 1 year(LOE B) If initial conservative strategy selected but patient has recurrent ischaemic symptoms/heart failure/arrythmias – diagnostic angiography recommended. Clopidogrel or Glycoprotein 2b/3a inhibitors should be added before angiography.

43. ANTICOAGULANT THERAPY CLASS 1 Anticoagulant therapy should be added as soon as possible For patients undergoing angiography/PCI – enoxaparin/UFH (LOE A) of Bivalirudin/ fondaparinux (LOE B) For conservative strategy: enaxaparin, UFH (LOE A), fondaparinux For patients with increased risk of bleeding with conservative strategy – fondaparinux

44. CLASS 2a Enoxaparin /fondaparinux vs UFH Enoxaparin/fondaparinux preferred except in those undergoing CABG within 24hrs (LOE B)

45. ADDITIONAL MANAGEMENT STRESS TEST should be performed for those managed conservatively. If stress test positive/ high risk – needs diagnostic angiography(Class 1 LOE A) If classed as low risk – need to continue aspirin indefinitely ( LOE A) Clopidogrel for at least 1 month(LOE A), ideally up to 1 year(LOE B)

46. UA/NSTEMI ALGORITHM- INVASIVE STRATEGY

47. UA/NSTEMI ALGORITHM –CONSERVATIVE STRATEGY

48. STEMI PHARMACOLOGICAL UPDATE: ANALGESIA – changes from 2004 guidelines MORPHINE: still remains Class 1 C for STEMI, titrated doses NSAIDS/COX 2 INHIBITORS: those on it should have it discontinued ( increased risk of mortality, re infarction, heart failure, myocardial rupture) Class 1 C NSAIDS should not be administered in hospital for MI (Class 3)

49. BETA BLOCKERS Modified recommendation Oral Beta Blockers should be initiated in first24rs, if no contra- indications (heart failure, risk of cardiogenic shock) Class 1 B Patients with early contraindications -> re- evaluated later for possible use Role of IV B blockers – used in hypertensive patients with STEMI Class 2a B Class 3 LOE A – IV B blockers should not be administrated to patients with heart failure, risk of cardiogenic shock

50. No major changes to reperfusion strategies. Emphasis on decreasing ischaemic time. Increase use of prehospital 12 lead ECG emphasised. In PCI capable hospital – door to PCI time 90 min (Class 1 A) In non PCI capable hospital – door to needle time 30 min or timeous transfer to PCI capable hospital. (Class 1 B)

51. REPERFUSION STRATEGY

52. FIBRINOLYTICS AVAILABLE FIBRINOLYTICS: STREPTOKINASE – 1.5mu infusion over 30min (1hour –ACLS) rtPA – accelerated infusion over 1.5hrs - 15mg IV bolus, 0.75mg/kg over 30 min, 0.5mg/kg over 1hr ANISTREPLASE – 30 U IV over 5 min TENECTEPLASE – 30 TO 50 MG RETEPLASE – 10 U IV bolus, ffd. 10U IV after 30 min WHICH FIBRINOLYTIC TO USE??? GISSI 2 trial – tPA vs Streptokinase, no difference in mortality, marginally higher stroke rate with tPA (1.3% vs 1%) GUSTO 1 trial – early vessel patency post infract assoc. with better survival. Accl. tPA/heparin cf comb. Streptokinase/tPA/heprain cf strep with IV vs S/C heparin Outcome – better flow rates with accl. tPA -> lower mortality rates

53. ASSENT 2 TRIAL – tenecteplase vs aTPA - tenecteplase was equally or minimally more effective, especially in those presenting > 4hrs after symptom onset. Fibrinolysis combined with glycoprotein 2b/3a inhibitors – no overall advantage (ASSENT 3, GUSTO 5 trials)

54. RESCUE PCI: CLASS 1 LOE B – angiography with +/- PCI in patients (<75 yrs)with cardiogenic shock, severe heart failure, ventricular dysrythmias Class 2a – persistent ischaemic symptoms post fibrinolysis, haemodynamic instability, electrical instability (LOE C) New recommendation – PCI for failed fibrinolytic therapy (less than 50% decrease in ST elevation in worst lead, 90min post fibrinolytic therapy, or large area of myocardium injured) LOE B Class 3 – angiography performed if invasive strategy contraindicated, or patient refusal (LOE C)

55. ANTICOAGULANT ADJUNCTS NEW RECOMMENDATIONS: CLASS 1 Patients undergoing fibrinolysis should be kept on anticoagulants for atleast 48 hrs and preferably the duration of hospital stay. LOE A Anti coagulants with proven efficacy: Unfractionated Heparin - keeping aPTT 1.5 – 2 sec above control (LOE C) Enoxaparin (Clexane) – initial dosage of 30mg IV bolus – ffd by 1mg/kg 12hrly, caution in renal impairment (LOE A) Fondaparinux – 2.5mg IV, ffd by 2.5mg dly S/C maintenance for duration of hospitalisation (LOE B)

56. ANTICOAGULANTS CLASS 2a recommendation to use anticoagulants in STEMI without reperfusion. UFH (LOE B) LMWH (LOE C) Fondaparinux (LOE B)

57. THIENOPYRIDINES CLASS I CLOPIDOGREL – now recommended in all STEMI patients in addition to aspirin, whether undergoing reperfusion or not. Dosage 75mg daily(LOE A) Duration -14 days (LOE B) CLASS 2 A In patients < 75yrs – Clopidogrel 300mg loading dose recommended(LOE C) Long term maintenance therapy should be considered, 75mg dly for 1 year (LOE C)

58. SECONDARY PREVENTION INCREASED FOCUS ON SECONDARY PREVENTION: SMOKING CESSATION DIET MODIFICATION/WT CONTROL BP CONTROL LIPID MANAGEMENT EXERCISE DIABETES MANAGEMENT

59. Despite good reperfusion strategies approx. 1/3 of patients worldwide miss out. Attributed to – delayed presentation, atypical presentation, complicated disease presentation, older age SYMPTOMS OF INFARCT BUT NO ESTABILISHED ECG CHANGES - keep in mind aortic dissection, GIT disease, other chest pathology

62. CONCLUSION With increase burden of CVD, and lack of health resources risk stratification becomes important. Emphasis should also be placed on primary &secondary prevention of ACS. Early intervention helps prevent complications, decreases morbidity & mortality The way forward – fully equipped CHEST PAIN OBSERVATION UNIT

63. REFERENCES EDITORS MARX ET AL, ROSEN’S EMERGENCY MEDICINE: CONCEPTS AND CLINICAL PRACTICE, 6 TH EDITION PAUL PD ET AL, KEY ARTICLES IN MANAGEMENT OF ACS & PCI -2007 UPDATE, PHARMACOTHERAPY 2007:27(12), 1722 -1750 WHITE HD, DEFINING THE LIMITS OF ACS, CARDIOLOGY AT THE LIMITS IV, EDITORS: OPIE LH, YELLON DM YUSUF S, THE GLOBAL EPIDEMIC OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, CARDIOLOGY AT THE LIMITS IV, EDITORS: OPIE LH, YELLON DM FOX KA, MANAGEMENT OF ACS: AN UPDATE, HEART.2004 JUNE, 90(6):698 -706 ANDERSON ET AL, ACC/AHA 2007 GUIDELINES FOR MXN OF U/A,NSTEMI – EXECUTIVE SUMMARY – DOWNLOADED content.onlinejacc.org SIX AJ ET AL, CHEST PAIN IN THE ER: VALUE OF THE HEART SCORE, NETH. HEART J. 2008 JUNE,16(6):191 -196

64. ANTMAN EM ET AL, 2007 FOCUSSED UPDATE OF ACC/AHA 2004 GUIDELINES FOR MAXN OF PATIENTS WITH STEMI, DOWNLOADED http://circ.ahajournals.orghttp://circ.ahajournals.org McCANN CJ ET AL, NOVEL BIOMARKERS IN EARLY DIAGNOSIS OF AMI COMPARED WITH CARDIAC TROPONIN T, EUROPEAN HEART JOURNAL 2008,29(23): 2843 -2850 KING III SB ET AL, 2007 FOCUSSED UPDATE OF ACC…..FOR PCI, JOURNAL OF AMERICAN COLLEGE OF CARDIOLOGY, VOL 51, NO 2, 2008