Ac Coronary Syndrome


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Ac Coronary Syndrome

  1. 1. Current Management of Acute Coronary Syndrome in a Non- Interventional Center
  2. 2. Definition <ul><li>Acute Coronary Syndrome: </li></ul><ul><li>Any constellation of clinical symptoms that are compatible with acute myocardial ischemia. </li></ul><ul><li>It encompasses AMI (ST-segment elevation and depression, Q wave and non-Q wave) as well as Unstable angina. </li></ul>
  3. 3. Acute Coronary Syndromes Unstable Angina Ischemic Chest Discomfort No ST Elevation ST Elevation Non -ST Elevation MI ST Elevation MI ECG Cardiac markers – +
  4. 4. Golden Hour <ul><li>Maximum damage to heart muscle </li></ul><ul><li>Maximum efficacy of treatment seen </li></ul><ul><li>Survival is best if clot buster drugs given within this period </li></ul><ul><li>“ Time is muscle and muscle is time” </li></ul>
  5. 5. Process of care in emergency department: 4 D’s <ul><li>Timed 0 : onset of symptoms </li></ul><ul><li>ED time 1: D oor [arrival at ED] </li></ul><ul><li>ED time 2: D ata </li></ul><ul><li> [initial ECG] </li></ul><ul><li>ED time 3: D ecision </li></ul><ul><li>[to administer thrombolytics] </li></ul><ul><li>ED time 4: D rug </li></ul><ul><li>[infusion of thrombolytic started </li></ul>Time interval 1 Time interval 2 Time interval 3 Door To Drug time
  6. 6. Door to Needle time <ul><li>< 30 min in 33% patients only </li></ul><ul><li>Adjusted odds ratio of death if Door to Needle time was </li></ul><ul><ul><li>61 - 90 min = 11% </li></ul></ul><ul><ul><li>> 90 min = 23 % </li></ul></ul><ul><li>11-23 % increased odds of developing EF < 40% if Door to Needle time was > 30 min. </li></ul><ul><li>Door to Ballon time > 2 hrs was ass. with 41-62 % increase in adjusted odds ratio of death. </li></ul>
  7. 7. Reducing treatment delays <ul><li>EMS system </li></ul><ul><li>Ambulance transport </li></ul><ul><li>Pre-hospital ECGs </li></ul><ul><li>Pre-hospital thrombolysis : only when a physician is present or if pre-hospital transport time is > 6o min </li></ul><ul><li>Heart attack awareness campaign </li></ul>
  8. 8. Emergency Room Triage in ACS <ul><li>Initial presentation </li></ul><ul><li>12 Lead ECG </li></ul><ul><li>Cardiac Enzymes </li></ul>
  9. 9. TRIAGE OF ACS Ischemic Chest Discomfort ST Elevation or New LBBB ECG s/o Ischemia ST dep, T inversion Non-diagnostic or Normal ECG Assess initial ECG Aspirin Baseline CK, CK-MB Assess C/I to thrombolysis Anti-ischemic therapy Reperfusion therapy [ thrombolyse or Primary PTCA ] Admit Anti-ischemic therapy Serial cardiac markers 2D Echo E/o ischemia / MI No Yes Discharge Admit Goal 10 minutes Goal < 30 min for STK or < 60 min for arrival in Cath Lab for PTCA
  10. 10. Criteria For The Diagnosis Of Acute Myocardial Infarction (AMI)  Biomarkers +  of the following Pathological findings of AMI Typical symptoms of AMI + one of the following Procedural myocardial damage Typical symptoms of myocardial ischemia No other findings required ST segment elevation in the ECG  cardiac biomarkers to prespecified levels; symptoms may be absent; ECG changes absent/nonspecific Q waves in the ECG   Increased levels of cardiac biomarkers   ST segment elevation or depression in the ECG       Modified from Alpert J, Thygesen K, et al: Towards a new definition of myocardial infarction for the 21st century. J Am Coll Cardiol 2000, in press.
  11. 11. Initial Presentation
  12. 12. Common Symptom History In Acute MI <ul><li>Chest Pain </li></ul><ul><ul><li>Location </li></ul></ul><ul><ul><ul><li>Usually substernal </li></ul></ul></ul><ul><ul><li>Quality </li></ul></ul><ul><ul><ul><li>Crushing or squeezing </li></ul></ul></ul><ul><ul><li>Radiation </li></ul></ul><ul><ul><ul><li>Either Arm, Neck, Jaw, Epigastrium, Or between Scapulae </li></ul></ul></ul><ul><ul><li>Duration </li></ul></ul><ul><ul><ul><li>Generally 30 minutes to several hours </li></ul></ul></ul><ul><li>Anginal Pain Equivalents </li></ul><ul><li>Dyspnoea </li></ul><ul><li>Marked weakness </li></ul><ul><li>Syncope </li></ul><ul><li>Accompanied diaphoresis, nausea, vomiting </li></ul>
  13. 13. No pain ; No gain <ul><li>In national registry of myocardial infarction [NRMI] 435,000 patients with proven acute MI, chest pain was absent at initial presentation [33%] </li></ul><ul><li>These pts </li></ul><ul><ul><li>were at least 7 years older; </li></ul></ul><ul><ul><li>higher proportion were women[49% vs 38%]; diabetics; had h/o prior heart failure </li></ul></ul><ul><ul><li>had longer delay before hospital admission; </li></ul></ul><ul><ul><li>were less likely to receive thrombolysis or primary PTCA; b-blockers, aspirin or heparin </li></ul></ul><ul><ul><li>Had higher in-hospital mortality [23.3% vs 9.3%] </li></ul></ul>
  14. 14. Recognition of High Risk Cases <ul><li>Demographic and historical factors associated with poor prognosis </li></ul><ul><ul><li>Age > 70 years </li></ul></ul><ul><ul><li>Female gender </li></ul></ul><ul><ul><li>History of Diabetes mellitus </li></ul></ul><ul><ul><li>Prior angina pectoris </li></ul></ul><ul><ul><li>Previous MI </li></ul></ul><ul><ul><li>Peterson ED et al. Ann Intern Med 126:561-582,1997 </li></ul></ul>
  15. 15. Electrocardiogram “standard of care”
  16. 16. ECG Patterns Normal 38% ST Depression 18% T Inversion 23% ST Elevation 11% LBBB 10% Hamm et al. NEJM 1997;337 ST Depression 57% Normal 13% T Inversion 13% ST Elevation 17% TIMI IIIb Investigators, Circulation 1994;89 In Acute Chest Pain In unstable angina
  17. 17. Prognostication through ECG <ul><li>ST elevation </li></ul><ul><ul><ul><li>decisive role regarding thrombolytic therapy </li></ul></ul></ul><ul><li>Worse prognosis / Increase mortality in </li></ul><ul><ul><ul><li>Anterior MI > Inferior MI </li></ul></ul></ul><ul><ul><ul><li>RVMI complicating IWMI </li></ul></ul></ul><ul><ul><ul><li>Multiple leads with ST elevation & high sum of ST elev. </li></ul></ul></ul><ul><ul><ul><li>Persistent advanced heart block </li></ul></ul></ul><ul><ul><ul><li>New IVCD (Bifascicular / trifascicular) </li></ul></ul></ul><ul><ul><ul><li>Persistent ST depression / Q waves in many leads </li></ul></ul></ul><ul><ul><ul><li>ST depression in anterior leads in IWMI </li></ul></ul></ul><ul><ul><li>NEJM 330:1211-1217, 1994 , Ann Intern Med 126:556;1997 </li></ul></ul>
  18. 18. Risk of MI/Death during 1 yr Followup based on ECG on Admission The RISC Study Group . J.Intern.Med.1993;234
  19. 19. Limitations of ECG <ul><li>It provides a snapshot view of a highly dynamic process. </li></ul><ul><li>Lack of perfect detection in areas of myocardium it supplies. </li></ul><ul><li>Small areas of ischemia or infarction may not be detected. </li></ul><ul><li>Conventional leads do not directly examine right ventricle, posterior basal or lateral walls very well. </li></ul><ul><li>Baseline changes like BBBs, early repolarization, LVH, & arrhythmias make interpretation difficult. </li></ul><ul><li>AMI in LCx territory are likely to have non-diagnostic ECG. </li></ul><ul><li>ECG is not very sensitive test & should always be considered a supplement to , rather than a substitute for, physician judgment. </li></ul>
  20. 20. Pseudo-infarction on ECG <ul><li>LVH </li></ul><ul><li>Conduction disturbance </li></ul><ul><li>Pre-excitation </li></ul><ul><li>Primary myocardial disease </li></ul><ul><li>Traumatic heart disease </li></ul><ul><li>Pericarditis </li></ul><ul><li>Early repolarization </li></ul><ul><li>Pneumothorax </li></ul><ul><li>Pulmonary embolism </li></ul><ul><li>I/C hemorrhage </li></ul><ul><li>Hyperkalemia </li></ul><ul><li>Amyloidosis </li></ul><ul><li>Sarcoid cardiac involvement </li></ul>
  21. 21. Cardiac Markers
  22. 22. TABLE 35-1 -- CAUSES OF MYOCARDIAL INFARCTION WITHOUT CORONARY ATHEROSCLEROSIS CORONARY ARTERY DISEASE OTHER THAN ATHEROSCLEROSIS Arteritis    Luetic    Granulomatous (Takayasu disease)    Polyarteritis nodosa    Mucocutaneous lymph node (Kawasaki) syndrome    Disseminated lupus erythematosus    Rheumatoid spondylitis    Ankylosing spondylitis Trauma to coronary arteries    Laceration    Thrombosis    Iatrogenic    Radiation (radiation therapy for neoplasia) Coronary mural thickening with metabolic disease or intimal    proliferative disease    Mucopolysaccharidoses (Hurler disease)    Homocysteinuria    Fabry disease    Amyloidosis    Juvenile intimal sclerosis (idiopathic arterial calcification of infancy)    Intimal hyperplasia associated with contraceptive steroids or with the postpartum period    Pseudoxanthoma elasticum    Coronary fibrosis caused by radiation therapy Luminal narrowing by other mechanisms    Spasm of coronary arteries (Prinzmetal angina with normal coronary arteries)    Spasm after nitroglycerin withdrawal    Dissection of the aorta    Dissection of the coronary artery EMBOLI TO CORONARY ARTERIES Infective endocarditis Nonbacterial thrombotic endocarditis Prolapse of mitral valve Mural thrombus from left atrium, left ventricle, or pulmonary veins Prosthetic valve emboli Cardiac myxoma Associated with cardiopulmonary bypass surgery and coronary arteriography Paradoxical emboli Papillary fibroelastoma of the aortic valve (&quot;fixed embolus&quot;) Thrombi from intracardiac catheters or guidewires CONGENITAL CORONARY ARTERY ANOMALIES Anomalous origin of left coronary from pulmonary artery Left coronary artery from anterior sinus of Valsalva Coronary arteriovenous and arteriocameral fistulas Coronary artery aneurysms MYOCARDIAL OXYGEN DEMAND-SUPPLY DISPROPORTION Aortic stenosis, all forms Incomplete differentiation of the aortic valve Aortic insufficiency Carbon monoxide poisoning Thyrotoxicosis Prolonged hypotension HEMATOLOGICAL (IN SITU THROMBOSIS) Polycythemia vera Thrombocytosis Disseminated intravascular coagulation Hypercoagulability, thrombosis, thrombocytopenic purpura MISCELLANEOUS Cocaine abuse Myocardial contusion Myocardial infarction with normal coronary arteries Complication of cardic catheterization Modified from Cheitlin M, et al: Myocardial infarction without atherosclerosis. JAMA 231:951, 1975. Copyright 1975, American Medical Association. MARKER MW (D) TIMES TO INITIAL ELEVATION (hr) MEAN TIME TO PEAK (NONTHROMBOLYSIS) TIME TO RETURN TO NORMAL RANGE MOST COMMON SAMPLING SCHEDULE hFABP 14,000-15,000 1.5 5-10 hr 24 hr On presentation, then 4 hr later Myoglobin 17,800 1-4 6-7 hr 24 hr Frequent; 1-2 hr after CP MLC 19,000-27,000 6-12 2-4 d 6-12 d Once at least 12 hr after CP cTnI 23,500 3-12 24 hr 5-10 d Once at least 12 hr after CP cTnT 33,000 3-12 12 hr-2 d 5-14 d Once at least 12 hr after CP MB-CK 86,000 3-12 24 hr 48-72 hr Every 12 hr×3 MM-CK tissue isoform 86,000 1-6 12 hr 38 hr 60-90 min after CP MB-CK tissue isoform 86,000 2-6 18 hr Unknown 60-90 min after CP Enolase 90,000 6-10 24 hr 48 hr Every 12 hr×3 LD 135,000 10 24-48 hr 10-14 d Once at least 24 hr after CP MHC 400,000 48 5-6 d 14 d Once at least >2 d after CP hFABP=heart fatty acid binding proteins; MLC=myosin light chain; cTnI=cardiac troponin I; cTnT=cardiac troponin T; MB-CK=MB isoenzyme of creatinine kinase (CK); MM-CK=MM isoenzyme of CK; LD=lactate dehydrogenase; MHC=myosin heavy chain; CP=chest pain
  23. 23. Appearance of Cardiac Markers in Blood Versus Time After Onset of Symptoms. <ul><li>Peak A: Myoglobin or CK-MB isoforms post AMI </li></ul><ul><li>Peak B: cardiac troponin post AMI </li></ul><ul><li>Peak C: CK-MB post AMI </li></ul><ul><li>Peak D: cardiac troponin after unstable angina. </li></ul>
  24. 24. Predictive Value of Troponin Rapid Testing <ul><li>Predischarge TMT + Troponin </li></ul><ul><li>If Both Normal--1 % risk of Death /MI at 5 Months </li></ul><ul><li>If both Abnormal --50 % risk of death/MI at 5 Months </li></ul>
  25. 25. Troponins <ul><li>30% patients with rest pain without ST- elevation and were diagnosed as unstable angina based on CPK_MB results are found to have elevated troponins, converting these to NSTEMI. </li></ul>
  26. 26. Clinical Status GISSI-1 (%) Killip Definition Incidence Control Lytic Class Mortality Mortality I No CHF 71 7.3 5.9 II S3 gallop or 23 19.9 16.1 basilar rales III Pulmonary edema 4 39.0 33.0 (rales >1/2 up) IV Cardiogenic shock 2 70.1 69.9 Killip T et al. Am J Cardiol 20:457;1967 GISSI. Lancet 1”397-401, 1986
  27. 27. Hospital Phase
  28. 28. Hospital Phase : Tools <ul><li>Risk stratification in CCU is done by </li></ul><ul><ul><li>Clinical findings </li></ul></ul><ul><ul><li>ECG monitoring </li></ul></ul><ul><ul><li>Invasive hemodynamic monitoring </li></ul></ul><ul><ul><li>LV Function - most important determinant of hospital mortality </li></ul></ul><ul><ul><li>Echocardiography – LVEF, diastolic function, hemodynamics, degree of MR, mechanical complications </li></ul></ul>
  29. 29. Hemodynamic Classification Forrester J et al. NEJM 295:1356:1976
  30. 30. Echocardiography <ul><li>Identification of location of infarction </li></ul><ul><li>Estimation of infarct size </li></ul><ul><li>Determination of LVEF </li></ul><ul><li>Assessment of diastolic function </li></ul><ul><li>Degree of MR </li></ul><ul><li>Recognition of mechanical complications </li></ul><ul><li>LVEF < 40% within 72 hrs of onset of AMI is associated with increase risk of death </li></ul><ul><li>Berning et al. Am J Cardiol 69:1538-44;1992 </li></ul>
  31. 31. Echocardiography <ul><li>Greater number of WMA correlated with </li></ul><ul><ul><ul><li>higher Killip class, </li></ul></ul></ul><ul><ul><ul><li>lower pO 2 , </li></ul></ul></ul><ul><ul><ul><li>higher CPK levels and </li></ul></ul></ul><ul><ul><ul><li>larger number of Q waves on ECG </li></ul></ul></ul><ul><ul><li>Romano et al </li></ul></ul><ul><li>30 day mortality </li></ul><ul><ul><ul><ul><li>WMA < 3 segments 3.5% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WMA 4-6 segments 12.9% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WMA 7-9 segments 18.3% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WMA > 9 segments 37.8% </li></ul></ul></ul></ul>Am J Cardiol 81(12A):13G-16G;1998
  32. 32. Mitral inflow patterns Normal Relaxation Defect Pseudo - Normalization Restrictive pattern A E <ul><li>Worse is the flow pattern, worse is the prognosis </li></ul><ul><li>A deceleration time < 130 msec indicates future development of CHF </li></ul><ul><li>Poulsen et al , Eur Heart J 1997;18:1882 </li></ul>
  33. 33. Complications <ul><li>LV systolic dysfunction </li></ul><ul><li>Rupture </li></ul>Free Wall VSD Papillary muscle rupture Subepicardial aneurysm
  35. 35. Complications <ul><li>Mitral regurgitation </li></ul>LV dilatation Papillary muscle dysfunction Papillary muscle rupture LV thrombus Pericardial effusion/tamponade RVinfarct LV outflow tract obstruction
  36. 36. Echo: value in ACS <ul><li>Echo provides new and useful information in 29% of the patients admitted to CCU </li></ul><ul><li>Decision about reperfusion strategy </li></ul><ul><li>ACE-I therapy (SAVE trial) </li></ul><ul><li>Unrecognized prior MI </li></ul><ul><li>Titrating beta-blockers </li></ul><ul><li>Need for invasive monitoring </li></ul><ul><li>Standby IABP support </li></ul>
  37. 37. Management <ul><li>Goals </li></ul><ul><li>Immediate relief of ischemia </li></ul><ul><li>Prevention of serious adverse outcomes </li></ul><ul><li>Approach </li></ul><ul><li>Anti-ischemic therapy </li></ul><ul><li>Anti-platelet therapy </li></ul><ul><li>Anti-coagulant therapy </li></ul><ul><li>Ongoing risk stratification </li></ul><ul><li>Invasive procedures </li></ul>
  38. 39. Anti-Ischemic therapy for Continuing Ischemia <ul><li>Bed rest with ECG monitoring </li></ul><ul><li>O 2 to maintain SaO 2 >90% </li></ul><ul><li>NTG IV </li></ul><ul><li>Beta-blockers </li></ul><ul><li>Morphine </li></ul><ul><li>IABP if ischemia or hemodynamic instability persists </li></ul><ul><li>ACE I for control of hypertension or LV dysfunction, after MI </li></ul>Class-I Recommendations, ACC/AHA practice guidelines
  39. 40. Anti Ischemic Therapy <ul><li>Nitrates </li></ul><ul><li>Beta Blockers </li></ul><ul><li>Calcium Channel Blockers </li></ul>
  41. 42. Beta Blockers in ACS * Eur H Journal 1985;6 # Lancet 1986;ii
  42. 43. Calcium Ch. Blockers in ACS Salim Yusuf, BMJ 1989; 299
  43. 44. Antiplatelet and Anticoagulation Therapy <ul><li>Oral Antiplatelet therapy </li></ul><ul><li>Aspirin </li></ul><ul><ul><li>Thienopyridines Ticlopidine Clopidogrel </li></ul></ul><ul><li>Heparins </li></ul><ul><ul><li>UFH </li></ul></ul><ul><ul><li>LMWH </li></ul></ul><ul><li>IV Antiplatelet therapy </li></ul><ul><li>Abciximab </li></ul><ul><li>Eptifibatide </li></ul><ul><li>Tirofiban </li></ul>
  44. 45. Anticoagulants Unfractionated Heparin (UFH) <ul><li>Most widely used antithrombotic agent </li></ul><ul><li>Recommendation is based on documented efficacy in many trials of moderate size </li></ul><ul><li>Meta-analyses of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleeding </li></ul>
  45. 46. Unfractionated Heparin (UFH) <ul><li>Disadvantages include: </li></ul><ul><li>Poor bioavailability </li></ul><ul><li>No inhibition of clot-bound thrombin </li></ul><ul><li>Dependent on antithrombin III (ATIII) cofactor </li></ul><ul><li>Frequent monitoring (aPTT) to ensure therapeutic levels </li></ul><ul><li>Rebound ischemia after discontinuation </li></ul><ul><li>Risk of heparin-induced thrombocytopenia (HIT) </li></ul>
  46. 47. Low-Molecular-Weight Heparin (LMWH) <ul><li>Fraction of standard (UFH) heparin </li></ul><ul><li>Advantages over UFH: </li></ul><ul><li>Greater bioavailability </li></ul><ul><li>No need to closely monitor </li></ul><ul><li>Resistant to inhibition by activated platelets </li></ul><ul><li>Lower incidence of HIT Enhanced anti-factor Xa activity </li></ul><ul><li>Effective subcutaneous administration </li></ul><ul><li>Enoxaparin, dalteparin, reviparin, nadroparin, fraxiparin </li></ul>
  47. 48. Role of Anticoagulants in ACS
  48. 49. New Anti coagulants in ACS
  49. 50. ESSENCE Trial (Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study) <ul><li>LMWH (enoxaparin)+ASA vs UFH+ASA </li></ul><ul><li>Patients:   angina at rest or non-Q-wave MI; </li></ul><ul><li>n = 3,171 </li></ul><ul><li>Composite triple endpoint:  death/nonfatal MI/RA </li></ul>
  50. 51. ESSENCE Trial incidence of death, MI, or recurrent angina N Eng J Med 1997;337:447-452 heparin enoxaparin Heparin enoxaparin n=1564 n=1607 n=1564 n=1607 19.8% 16.6% P=0.019 23.3% 19.8% P=0.016 Day 14 Day 30
  51. 52. AntiThrombotic Tt for ACS <ul><li>Anticoagulants </li></ul><ul><ul><ul><ul><li>Heparin </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>UFH </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>LMW </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Hirudin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Coumarins </li></ul></ul></ul></ul><ul><li>Antiplatelets </li></ul><ul><ul><ul><ul><li>Aspirin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Ticlopidine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Gp IIb/IIIA Inhibitors </li></ul></ul></ul></ul><ul><li>Thrombolytics </li></ul>
  52. 53. Anti Platelet Tt in ACS <ul><li>Aspirin - - Inhibits cyclo-oxygenase in platelets </li></ul><ul><li>Ticlopidine --- Inhibits the ADP receptor on the platelet surface </li></ul><ul><li>Gp iib/iiia receptor antagonist </li></ul>
  53. 54. Aspirin <ul><li>In AMI, ASA reduced the risk of death by 20-25% In UA, ASA reduced the risk of fatal or nonfatal MI by 71% during the acute phase, 60% at 3 months, and 52% at 2 years </li></ul>
  54. 55. Incidence of Ischemic Events No aspirin (early 1980s) Aspirin Aspirin + Heparin 16% 12% 9% Incidence of death and MI
  55. 56. <ul><li>Not Perfect </li></ul><ul><li>Patients on ASA may present with ACS </li></ul><ul><li>ASA non-responders 20-30% </li></ul><ul><li>Not adequate alone for stent implantation </li></ul><ul><li>Side effects </li></ul>
  56. 57. Thienopyridines <ul><li>Ticlopidine </li></ul><ul><li>Clopidogrel </li></ul><ul><ul><li>Block ADP receptor resulting in inhibition of transformation of GP IIb/IIIa into its high affinity state </li></ul></ul>
  57. 58. Aspirin & Ticlopidine in ACS
  58. 59. CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) <ul><li>19,185 patients randomly assigned to clopidogrel (75 mg/d) or to aspirin (325 mg/d) </li></ul><ul><li>Entry criteria: recent MI, recent ischemic stroke and symptomatic PAD </li></ul><ul><li>Follow up for 1-3 years </li></ul><ul><li>8.7% RR in the combined incidence of stroke, MI, or death (P=.043) with clopidogrel </li></ul><ul><li>Patients with MI did better with aspirin </li></ul><ul><li>Patients with PVD or stroke did better with clopidogrel </li></ul><ul><li>Lancet 1996;348:1329-1339 </li></ul>
  59. 61. CURE <ul><li>Randomized, double-blind, parallel group, clinical trial of clopidogrel vs placebo in patients with ACS </li></ul><ul><li>All patients receive ASA (75-325 mg) </li></ul><ul><li>International trial (28 countries) </li></ul><ul><li>12,562 patients (482 Hospitals) Central randomization </li></ul><ul><li>3-12 month Rx and follow-up </li></ul><ul><li>Main outcomes: CV death/MI, stroke + refractory ischemia </li></ul>
  60. 65. Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) <ul><li>Clopidogrel is a class I indication for treatment unstable angina, even when early coronary intervention is not being considered. </li></ul><ul><li>The treatment might be continued for at least 9 months. </li></ul><ul><li>If a coronary intervention is performed, clopidogrel should be started at 300 mg and continued for at least 1 month at 75 mg/d. In patients not at high risk for bleeding, clopidogrel should probably be continued for 9 months. </li></ul><ul><li>Clopidogrel has been associated with rare cases of thrombotic thrombocytopenic purpura. </li></ul><ul><li>If patients cannot tolerate aspirin or clopidogrel, warfarin (Coumadin) can be used and titrated to an international normalized ratio of 2.0 to 3.0 in post–myocardial infarction patients. </li></ul>
  61. 66. New Agents <ul><li>Other antithrombin agents such as lepirudin (Refludan), argatroban (Novastan), and the low-molecular-weight heparin dalteparin (Fragmin) need further study before they can be recommended in this setting. </li></ul><ul><li>Newer drugs are currently under investigation, including nicorandil, * trimetozine † , and fasudil † . </li></ul><ul><li>Newer markers for prognosis and stratification of patients with angina pectoris include </li></ul><ul><ul><ul><li>Brain natriuretic peptide (TIMI-16) </li></ul></ul></ul><ul><ul><ul><li>Annexin B. </li></ul></ul></ul>
  62. 67. Thrombotic Process – Pathophysiology Platelet Aggregation Ruptured Plaque Fibrinogen VWF VWF GP II b/ III a Receptor GP I b Receptor
  63. 68. IV Anti-platelet Therapy <ul><li>GP IIb/IIIa inhibitors </li></ul><ul><li>abciximab (monoclonal antibody) </li></ul><ul><li>eptifibatide (peptide inhibitor) </li></ul><ul><li>lamifiban and tirofiban (non-peptides) </li></ul>
  64. 74. <ul><li>Conclusive evidence of early benefit of GP IIb/IIIa inhibitors during medical treatment in acute coronary syndromes without persistent ST-segment elevation. </li></ul><ul><li>In addition, in patients subsequently undergoing PCI, GP IIb/IIIa inhibition protects against myocardial damage associated with the intervention. </li></ul>
  65. 75. Abciximab in ACS
  66. 77. IV GP IIb/IIIa ACS Trials (1998-2000) <ul><li>Patients undergoing PCI have the greatest reduction in events </li></ul><ul><li>Little data to support use to reduce complications in the absence of PCI </li></ul><ul><li>Should be used in high risk patients (ST changes, elevated troponin, refractory symptoms) as a bridge to catheterization </li></ul>
  67. 78. Recommendations for Antiplatelet & Anticoagulation Therapy <ul><li>Class I </li></ul><ul><li>1. Antiplatelet therapy should be initiated promptly. Aspirin is the first choice and is administered as soon as possible after presentation and is continued indefinitely. (Level of Evidence: A) </li></ul><ul><li>2. Clopidogrel should be administered to patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A) </li></ul><ul><li>3. In hospitalized patients in whom an early noninterventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (Level of Evidence : A) and for upto 9 months (Level of Evidence : B) </li></ul>
  68. 79. <ul><li>4. In hospitalized patients for whom a PCI is planned, clopidogrel should be started and continued for at least 1 month (Level of Evidence : A) and for up to 9 months in patients who are not at high risk for bleeding (Level of Evidence : B) </li></ul><ul><li>5. In patients taking clopidogrel in whom CABG is planned, if possible the drug should be withheld for at least 5 days, and preferably for 7 days. (Level of Evidence :B) </li></ul><ul><li>6. Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy with ASA and/or clopidogrel. (Level of Evidence : A) </li></ul><ul><li>7. A platelet GP IIb/IIIa receptor antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI (Level of Evidence: A) </li></ul>
  69. 81. Early Conservative vs Invasive Strategies Recommendations Class I <ul><li>An early invasive strategy in patients with UA/NSTE-MI and any of the following high risk indicators. (Level A) </li></ul><ul><ul><li>Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy </li></ul></ul><ul><ul><li>Elevated TnT or TnI </li></ul></ul><ul><ul><li>New or presumably new ST-segment depression </li></ul></ul><ul><ul><li>Recurrent angina/ischemia with CHF symptoms, an S3 gallop, pulmonary edema, worsening rales, or new or worsening MR </li></ul></ul><ul><ul><li>High-risk findings on noninvasive stress testing </li></ul></ul><ul><ul><li>Depressed LV systolic function (EF < 0.40) </li></ul></ul><ul><ul><li>Hemodynamic instability </li></ul></ul><ul><ul><li>PCI within 6 months </li></ul></ul><ul><ul><li>Prior CABG </li></ul></ul>
  70. 82. <ul><li>2. In the absence of these findings, either an early conservative or an early invasive strategy in hospitalized patients without contraindications for revascularization (Level of Evidence: B) </li></ul>
  71. 83. CASE 1 <ul><li>64 years, male presented with worsening angina for 2 weeks </li></ul><ul><li>ST depression inferiorly </li></ul><ul><li>Cardiac enzymes negative </li></ul><ul><li>Pre-treated with clopidogrel, in addition to ASA, UFH, metoprolol, ISDN and atorvastatin </li></ul>
  72. 85. CASE 2 <ul><li>62 years old female with HTN, DM, CABG </li></ul><ul><li>NSTEMI 10 days earlier </li></ul><ul><li>Initially treated with early conservative approach </li></ul><ul><li>Transferred due to recurrent angina (PIA) </li></ul>
  73. 87. Post discharge Care <ul><li>“ ABCDE” </li></ul><ul><li>A – Antiplatelets & Antianginals </li></ul><ul><li>B – Beta blocker, Blood pressure control </li></ul><ul><li>C – Cholesterol lowering, Cigarettes cessation </li></ul><ul><li>D – Diabetes control, Diet </li></ul><ul><li>E – Education & Exercise </li></ul>
  74. 88. POST INFARCT REMODELING Lessened Wall stress Increased Wall Stress No prevention LV dilation and remodeling LV failure WALL STRESS = Pressure x Radius 2 x (wall thickness) ACE inhibition Beta-blocker LV Smaller Less failure
  75. 89. ACE INHIBITORS Dzau-Braunwald model RISK FACTORS Hypertension LVH Atheroma Ischemia Thrombosis Sudden Death Infarction Reinfarction Loss of muscle Remodeling LV Failure - - - - - - - = ACE inhibitor effect
  76. 90. Future Directions <ul><li>CURE Study --- Role of Clopidogrel + Aspirin vs Aspirin alone </li></ul><ul><li>GUSTO 4 -- Abciximab </li></ul><ul><li>SYMPHONY --- Sidrafiban in ACS </li></ul><ul><li>OASIS-2 --- Warfarin </li></ul>
  77. 91. INDICATIONS OF PRIMARY PTCA <ul><li>Cardiogenic Shock </li></ul><ul><li>Large area of myocardium at risk </li></ul><ul><li>Thrombolysis contraindicated </li></ul><ul><li>Alternative to thrombolysis </li></ul>
  78. 92. Interventions in ACS <ul><li>Rationale </li></ul><ul><li>Prognosis of ACS is worse than Stable angina </li></ul><ul><li>Inhospital death / Reinf. = 5 - 10 % </li></ul><ul><li>Ist Mo Death / Reinf. = 5 - 10 % </li></ul>
  79. 93. PTCA in ACS <ul><li>TIMI III B </li></ul><ul><li>1473 pts randomised </li></ul>Early Invasive Conservative Mortality/Reinf 6 wks 7.2 % 7.8 % 1 Yr 10.8% 12.2%
  80. 94. PTCA in ACS VANQWISH TRIAL 916 Pts. Of UA Early Invasive Conservative 24 % 19% 1 yr Mortality or Reinf
  81. 95. PTCA in ACS FRISC 2 2457 Pts of ACS Early Invasive Tt Selective Invasive Tt 9.5 % 12 % 6 Mo Death or Reinf. Procedural 1.2 % 0.4 % Mortality
  82. 96. CABG in ACS
  83. 97. Future Directions <ul><li>RITA 3 - is comparing early invasive Tt with conservative tt. In ACS, in pts ttd. With LMWs </li></ul><ul><li>TACTICS- Early invasive vs conservative tt TIMI 18 with IV UFH Heparin + IV ReoPro </li></ul>
  85. 99. Phases & Lesion Morphology of Atherosclerosis American Heart Assn. Committee on Vascular Lesions
  86. 100. AMI: Parameters influencing prognosis Acute MI At Presentation In Hospital At Discharge Size of infarct Recurrent ischemia LV systolic dysfunction Diastolic dysfunction Mechanical complications Residual ischemia LV dysfunction Risk of arrhythmia Age Gender ECG features Concomitant Risk factors Clinical status
  87. 106. TIMI myocardial perfusion grade and mortality
  88. 107. Second International Study of Infarct Survival (ISIS-2).
  89. 108. Mortality differences during days 0 to 35 subdivided by presentation features in nine trials of thrombolytic therapy
  90. 109. TIMI Risk Score for STEMI for predicting 30-day mortality
  91. 112. Acute Coronary Syndromes Spectrum Acute Coronary Syndromes No ST elevation ST elevation Enzymes not  Enzymes  USA NSTEMI STEMI
  92. 114. Treatment of ACS <ul><li>All patients receive aspirin </li></ul><ul><li>Clopidogrel is also favored as an adenosine-mediated platelet blocker, particularly in patients with aspirin allergy. </li></ul><ul><li>ESSENCE trial (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q Wave Coronary Events) has suggested a preference for LMWH specifically, enoxaparin (Lovenox) over unfractionated heparin in ACS </li></ul><ul><li>Finally, a platelet glycoprotein IIb/IIIa inhibitor is needed. </li></ul><ul><li>Glycoprotein IIb/IIIa receptor blockers have been studied with simultaneous use of unfractionated heparin and aspirin. Most of the trials with these agents have involved coronary interventions and have shown significant benefit. </li></ul><ul><li>If no intervention is planned, abciximab is not indicated. </li></ul><ul><li>Currently, tirofiban and eptifibatide are useful in patients with continuing ischemia when no percutaneous intervention is planned. These latter two medications are also indicated in patients with continuing ischemia or other high-risk features in whom a percutaneous intervention is planned. </li></ul>
  93. 115. Rx of ACS <ul><li>TACTICS trial and TIMI-18 compared an early invasive and a conservative strategy in patients treated with the tirofiban & showed that an early invasive strategy reduces the incidence of major cardiac events. </li></ul><ul><li>The data for high-risk AMI and non–Q wave MI suggest that angiography should be part of the early plan. </li></ul><ul><li>The data for unstable angina with no elevation in biochemical markers are less clear. </li></ul><ul><li>Because of cost considerations, abciximab with coronary intervention is recommended in high-risk patients. </li></ul><ul><li>In intermediate-risk patients, regardless of whether they are candidates for coronary intervention, tirofiban or eptifibatide is recommended. </li></ul><ul><li>Low-risk patients may not require either of these agents, but they should receive heparin, probably low molecular-weight heparin, aspirin, and clopidogrel at a dose of 300 mg to start and then 75 mg/d for at least 30 days. </li></ul><ul><li>In addition, a “statin” should be started in that hospitalization (MIRACL) if LDL cholesterol is greater than 130 mg/dL. </li></ul>
  94. 116. Antithrombotic Drug Therapy Abciximab (ReoPro) with unfractionated heparin and aspirin 0.25-mg/kg intravenous bolus followed by an infusion of 0.125 μg/kg/min for 12–24 h up to 10 mg/min Eptifibatide (Integrilin) with unfractionated heparin and aspirin 180-μg/kg bolus followed by an infusion of 2 μg/kg/min up to 72 h for intervention. Max 15 mg/h Tirofiban (Aggrastat) with unfractionated heparin and aspirin 0.4 μg/kg/min × 30 min 0.1-μg/kg/min infusion × 48 h up to 108 h (PRISM-Plus) Enoxparin (clexane) 1 mg/kg q12 h Clopidogrel (Plavix) 300 mg initially, followed by 75 mg/d
  95. 117. Findings in High-Risk Patients <ul><li>Recurrent ischemia at rest or low levels of activity with medical management </li></ul><ul><li>High-risk noninvasive stress testing with depressed ejection fractions, </li></ul><ul><li>Extensive wall motion abnormalities </li></ul><ul><li>Hemodynamic instability </li></ul><ul><li>Sustained ventricular tachycardia </li></ul><ul><li>Recent revascularization with coronary intervention or coronary bypass graft surgery </li></ul>
  96. 118. Predictive Value of Troponins in ACS
  97. 119. Initial Presentation : Clinical The GUSTO Pyramid: 30 Day Mortality Model Lee et al. Circulation 1995;91:1659-1668 Influence of Clinical characteristics on 30 day mortality in thrombolyzed patients with STEMI Age (31%) Systolic Blood Pressure (24%) Killip Class (15%) Heart Rate (12%) MI Location (6%) Prior MI (3%) Age x Killip (1.3%) Height (1.1%) Diabetes (1%) Time-to-Rx (1%) Smoker (0.8%) Weight (0.8%) Accel t-PA (0.8%) Prior CABG (0.8%) HTN (0.6%) H/o CV D (0.4%)
  98. 120. Initial Presentation TIMI Risk Score for STEMI Morrow et al. In TIME II substudy. Circulation 2000; 102:2031-2037 1 Yr Mortality Score 0 - 1%; Score >8 - 17%
  99. 121. Painful facts <ul><li>40-60% patients presenting to ER with chest pain and later having confirmed MI have non-diagnostic ECGs. </li></ul><ul><ul><ul><li>Roberts & Kleiman , Circ 1994;89:872-881 </li></ul></ul></ul><ul><li>70-80% patients with non-Q MI present with ST depression only and 80% of these have subtotal coronary occlusion. Boden et al, JACC 1987;9:61A </li></ul>
  100. 122. ECG : prognostication GUSTO I outcome based on ECG 6.7%  ST II, III, aVF only distal RCA or LCx br. Small inferior 10.2%  ST V 1-4 or  ST I, aVL, V 5-6 beyond / in diagonal LAD (Distal) / diagonal 12.4%  ST V 1-6 , I, aVL before diagonal LAD (Mid) 25.6%  ST V 1-6 , I, aVL, fascicular or BBB before septal LAD (Prox) 8.4%  ST II, III, aVF and V 1 ,V 3 R,V 4 R or V 5-6 or R >S V 1-2 proximal RCA or LCX Moderate-to- large inferior (post, lat, RV) 1-Year mortality ECG Occlusion Site Category
  101. 123. Admission ECG Prognostic Value for Triaging GUSTO IIb Trial Eur H. J 1997
  102. 124. Clinical presentation <ul><li>Typical Angina </li></ul><ul><ul><ul><li>Criteria 1 to 3 all positive </li></ul></ul></ul><ul><ul><ul><li>Any 4 criteria positive </li></ul></ul></ul><ul><li>Atypical Angina </li></ul><ul><ul><ul><li>Any 2 criteria positive </li></ul></ul></ul><ul><ul><ul><li>Only criteria 4 to 6 positive </li></ul></ul></ul><ul><li>Nonanginal Chest Pain </li></ul><ul><ul><ul><li>Only 1 criteria positive </li></ul></ul></ul><ul><li>Ischemic chest pain </li></ul><ul><li>Retrosternal location </li></ul><ul><li>Radiation to jaw, left arm, or neck </li></ul><ul><li>Absence of other causes of chest pain </li></ul><ul><li>Precipitated by exercise </li></ul><ul><li>Brief duration </li></ul><ul><li>Relieved promptly by rest or nitroglycerin </li></ul>