Acute Myocardial Infarction (Acute MI) Prof. Arthur Pollak, M.D. Director, Acute Cardiac Care Center Director of Clinical Research Heart Institute Hadassah – Hebrew University Medical Center

Acute coronary syndromes Acute coronary syndromes. The longitudinal section of an artery depicts the time line of atherogenesis from a normal artery (1), to lesion initiation and accumulation of extracellular lipid in the intima (2), to the evolution to the fibrofatty stage (3), and to lesion progression with procoagulant expression and weakening of the fibrous cap (4). An ACS develops when the vulnerable or high-risk plaque undergoes disruption of the fibrous cap (5); disruption of the plaque is the stimulus for thrombogenesis. Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth (6). (Modified from Libby P: Circulation 104:365, 2001; Hamm CW, Bertrand M, Braunwald E: Lancet 358:1533, 2001; Davies MJ: Heart 83:361, 2000; and Antman EM, Anbe DT, Armstrong PW, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction]. Circulation 110:e82, 2004.)

Atherosclerosis is a Generalized Disease

Comparison of Age at First Myocardial Infarction Among Women and Men Across Geographic Regions MEDIAN AGE, WOMEN MEDIAN AGE, MEN Western Europe 68 (59-76) 61 (53-70) Central and eastern Europe 68 (59-74) 59 (50-68) North America 64 (52-75) 58 (49-68) South America and Mexico 65 (56-73) Australia and New Zealand 66 (59-74) 58 (50-67) Middle East 57 (50-65) 50 (44-57) Africa 56 (49-65) 52 (46-61) South Asia 60 (50-66) 52 (45-60) China and Hong Kong 67 (62-72) 60 (50-68) Southeast Asia and Japan 63 (56-68) 55 (47-64) Yusuf S: The INTERHEART Study. Lancet 2004;364:937

Age distribution in Hadassah CCU

RISK FACTORS FOR CAD %

NUMBER OF CORONARY ARTERIES OCCLUDED > 80% NUMBER OF CORONARY ARTERIES INVOLVED

The Effect of Race & Sex on Physicians’ Recommendations for Cardiac Catheterization Referral for Catheterization Race & sex influence how physicians interpret & manage chest pain Schulman KA, et al. NEJM 1999;340:618-616

Atheroma Morphology by Ultrasound “Soft” Lipid-Laden Plaque “Hard” Fibrous Plaque

Plaque Rupture

Acute Myocardial Infarction

Acute coronary syndromes Acute coronary syndromes. The longitudinal section of an artery depicts the time line of atherogenesis from a normal artery (1), to lesion initiation and accumulation of extracellular lipid in the intima (2), to the evolution to the fibrofatty stage (3), and to lesion progression with procoagulant expression and weakening of the fibrous cap (4). An ACS develops when the vulnerable or high-risk plaque undergoes disruption of the fibrous cap (5); disruption of the plaque is the stimulus for thrombogenesis. Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth (6). Following disruption of a vulnerable or high-risk plaque, patients experience ischemic discomfort resulting from a reduction of flow through the affected epicardial coronary artery. The flow reduction may be caused by a completely occlusive thrombus (bottom half, right) or subtotally occlusive thrombus (bottom half, left). Patients with ischemic discomfort may present with or without ST-segment elevation on the ECG. Of patients with ST-segment elevation, most ultimately develop a Q-wave MI (QwMI), whereas a few develop a non–Q-wave MI (NQMI). Patients who present without ST-segment elevation are suffering from unstable angina or NSTEMI, a distinction that is ultimately made on the presence or absence of a serum cardiac marker such as CK-MB or a cardiac troponin detected in the blood. Most patients presenting with NSTEMI ultimately develop an NQMI on the ECG; a few may develop a QwMI. The spectrum of clinical presentations ranging from unstable angina through NSTEMI and STEMI are referred to as the acute coronary syndromes. Dx = diagnosis. (Modified from Libby P: Circulation 104:365, 2001; Hamm CW, Bertrand M, Braunwald E: Lancet 358:1533, 2001; Davies MJ: Heart 83:361, 2000; and Antman EM, Anbe DT, Armstrong PW, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction]. Circulation 110:e82, 2004.)

The Normal Heart Acute anterior wall MI

Recent large Antero-Septal Myocardial Infarction

Ebers Papyrus

Clinical Presentation Typical Chest Pain pressure, heaviness, burning irradiation to arms, neck, jaw, upper abdomen, sometimes to the back Shortness of breath pulmonary congestion → pulmonary edema Nausea, Vomiting Cold sweating Dizziness → look for arrhythmias Anxiety, fear of death (!) Obtain ECG as quickly as possible (< 10 min) !

Physical examination Pallor Cold and clammy extremities Cold sweat on forehead and palms Bilateral crackles / crepitations / rales on lung auscultation (mostly basal) Muffled heart sounds, sometimes S4 Apical systolic murmur → look for mitral regurgitation Pulse: tachycardia , bradycardia Blood pressure: high , low

Anterior ST segment elevation ECG on admission: Anterior ST segment elevation

ECG - on admission

Pharmacologic dissolution of thrombus in infarct-related artery Pharmacologic dissolution of thrombus in infarct-related artery. This schematic view is of a longitudinal section of an infarct-related artery at the level of the obstructive thrombus. Following rupture of a vulnerable plaque (bottom center), the coagulation cascade is activated, ultimately leading to the deposition of fibrin strands (blue curvilinear arcs); platelets are activated and begin to aggregate (transition from flat discs, representing inactive platelets, to green spiked-ball elements, representing activated and aggregating platelets). The mesh of fibrin strands and platelet aggregates obstructs flow (normally moving from left to right) in the infarct-related artery; this would correspond to TIMI grade 0 on angiography. Pharmacologic reperfusion is a multipronged approach consisting of fibrinolytic agents that digest fibrin, antithrombins that prevent the formation of thrombin and inhibit the activity of thrombin that is formed, and antiplatelet therapy. (Courtesy of Luke Wells, the Exeter Group, New York, NY.)

Thrombolysis

Importance of time to reperfusion in patients undergoing PPCI for STEMI NCDR - National Cardiovascular Data Registry (USA) Importance of time to reperfusion in patients undergoing primary PCI for STEMI. B, Based on data from 43,801 patients, this depicts the adjusted in-hospital mortality rate as a function of door-to-balloon time. Estimated mortality ranged from 3% with a door-to-balloon time of 30 minutes to 10.3% for patients with a door-to-balloon time of 240 minutes. NCDR = National Cardiovascular Data Registry. (Data from Cannon CP, Gibson CM, Lambrew CT, et al: Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283:2941, 2000; and Rathore SS, Curtis J, Chen J, et al: Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: National cohort study. BMJ 338:b1807, 2009.) Cannon CP. JAMA 2000;283:2941 ;; Rathore SS. BMJ 2009;338:b1807

Importance of time to reperfusion in patients given fibrinolysis for STEMI NCDR - National Cardiovascular Data Registry (USA) Importance of time to reperfusion in patients undergoing fibrinolysis for STEMI. A, Graph based on data from 85,589 patients treated with fibrinolysis. For every 30-minute delay, there is a progressive increase in the in-hospital mortality rate. NCDR = National Cardiovascular Data Registry. (Data from Cannon CP, Gibson CM, Lambrew CT, et al: Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283:2941, 2000; and Rathore SS, Curtis J, Chen J, et al: Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: National cohort study. BMJ 338:b1807, 2009.) Cannon CP. JAMA 2000;283:2941 ;; Rathore SS. BMJ 2009;338:b1807

Time to thrombolysis and 35-day mortality The importance of time to thrombolysis in acute myocardial infarction and the absolute reduction in 35-day mortality in a meta-analysis of over 50,000 patients. The benefit from thrombolytic therapy is greatest when it is administered within two hours of symptom onset. The survival benefit is progressively reduced as the delay in therapy increases; after two hours, the benefit from thrombolytic therapy fits a linear function (black line) in which the benefit falls by approximately 1.6 lives per 1000 patients per hour of treatment delay. (Data from Boersma E, Maas ACP, Simoon ML. Lancet 1996; 348:771).

STEMI – time is muscle Major components of time delay between onset of infarction and restoration of flow in the infarct-related artery. Plotted sequentially from left to right are the time for patients to recognize symptoms and seek medical attention, transportation to the hospital, in-hospital decision making and implementing reperfusion strategy, and time for restoration of flow once the reperfusion strategy has been initiated. The time to initiate fibrinolytic therapy is the door-to-needle (D-N) time; this is followed by the period of time required for pharmacological restoration of flow. More time is required to move the patient to the catheterization laboratory for a PCI procedure, referred to as the door-to-balloon (D-B) time, but restoration of flow in the epicardial infarct-related artery occurs promptly after PCI. Bottom, Various methods for speeding the time to reperfusion are shown, along with the goals for the time intervals for the various components of the time delay. (Modified from Antman EM, Anbe DT, Armstrong PW, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction]. Circulation 110:e82, 2004.)

Reperfusion Therapy Primary Percutaneous Coronary Intervention (PPCI) – preferred! (especially in cardiogenic shock, heart failure, arrhythmia, late presentation) Thrombolytic Therapy – Fibrinolysis – if early! Tissue Plasminogen Activator (tPA) Streptokinase Risk of Bleeding → Contraindications: History of Intracranial Hemorrhage History of Ischemic Stroke within 3 months Cerebral vascular malformation or intracranial malignancy Suspected Aortic Dissection Active bleeding or known bleeding diathesis Significant closed-head or facial trauma within 3 months Traumatic or prolonged (>10 min) cardiac resuscitation

Coronary Angiogram 1 5 2 LAD 7 LCX 11 RCA 3 6 12 8 9 4 13 15 10 14

Thrombolysis Angioplasty

Isolated LAD Lesion

Reperfusion Therapy Primary Percutaneous Coronary Intervention (PPCI) – preferred! (especially in cardiogenic shock, heart failure, arrhythmia, late presentation) Thrombolytic Therapy – Fibrinolysis – if early! Tissue Plasminogen Activator (tPA) Streptokinase Risk of Bleeding → Contraindications: History of Intracranial Hemorrhage History of Ischemic Stroke within 3 months Cerebral vascular malformation or intracranial malignancy Suspected Aortic Dissection Active bleeding or known bleeding diathesis Significant closed-head or facial trauma within 3 months Traumatic or prolonged (>10 min) cardiac resuscitation

TIMI grade 3 coronary flow is associated with improved survival In the GUSTO-I trial, the 30-day mortality rate after thrombolysis for acute ST elevation myocardial infarction varied with the degree of vessel patency achieved. The mortality was lowest (4.3 percent) in patients with TIMI grade 3 (normal) flow in the infarct-related artery at 90 minutes. Partial restoration of flow (TIMI grade 2) did not improve outcomes compared to no or or faint flow (TIMI grade 0 or 1). (Data from The GUSTO Investigators. N Engl J Med 1993; 329:673.)

Medical therapy (initial) Oxygen (if O2 saturation < 95%) Aspirin (300-325 mg) to be chewed Sublingual Nitroglycerine (tablets or spray) Morphine sulfate (2-4 mg) I.V. (intravenous) Furosemide (40 mg) if pulmonary congestion Beta blocker (5 mg metoprolol I.V., repeat X3) High-dose statin (atorvastatin 80 mg orally) Treat ventricular arrhythmia promptly (!) Obtain blood for cardiac biomarkers (Troponin-T, CPK, hemoglobin, electrolytes, coagulation, kidney and liver function)

Adding Clopidogrel to Aspirin in STEMI (COMMIT trial) Impact of addition of clopidogrel to aspirin (ASA) in STEMI patients. B, Effect of the addition of clopidogrel on in-hospital mortality after STEMI. These time-to-event curves show a 0.6% reduction in mortality in the group receiving clopidogrel plus aspirin (n = 22,961) compared with placebo plus aspirin (n = 22,891) in the COMMIT trial. (B modified from Chen ZM, Jiang LX, Chen YP, et al: Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 366:1607, 2005.)

TRITON – TIMI 38: patients with ACS undergoing PCI 13,608 patients (10,074 UA/NSTEMI ; 3,534 STEMI) A, Comparison of efficacy (top) and safety (bottom) in the TRITON–TIMI 38 trial, which compared prasugrel with clopidogrel in patients with ACS undergoing PCI. HR = hazard ratio; NNH = number of patients needed to be treated to cause harm (TIMI major bleed); NNT = number of patients needed to prevent one primary endpoint event. (From Wiviott SD, Braunwald E, McCabe CH, et al: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001, 2007.)  Wiviott SD. TRITON – TIMI 38. N Engl J Med 2007;357:2001

TRITON – TIMI 38: patients with STEMI undergoing PCI A, Efficacy and safety of prasugrel among the subgroup of patients with STEMI enrolled in a randomized clinical trial of prasugrel compared with clopidogrel in patients undergoing PCI after presentation with acute coronary syndrome. Treatment with prasugrel was associated with a 21% relative reduction in the risk cardiovascular death, myocardial infarction, or stroke during 15 months of follow-up. Major bleeding was increased with prasugrel in the trial overall, but not among patients with ST-elevation myocardial infarction. CV = cardiovascular; NNT = number needed to treat. (A from Montalescot G, Wiviott SD, Braunwald E, et al: Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-segment elevation myocardial infarction [TRITON-TIMI 38]: Double-blind, randomised controlled trial. Lancet 373:723, 2009)

18,624 patients (10,174 UA/NSTEMI ; 8,430 STEMI) K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 18,624 patients (10,174 UA/NSTEMI ; 8,430 STEMI) 13 12 Clopidogrel 11.7 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 NNT = 54 3 2 1 HR 0.84 (95% CI 0.77–0.92), p=0.0003 The primary endpoint of the PLATO trial—a composite of death from cardiovascular (CV) causes, myocardial infarction (MI), or stroke—occurred significantly less often in the ticagrelor group than in the clopidogrel group (9.8% versus 11.7% at 12 months; HR, 0.84; 95% CI, 0.77 to 0.92; P < 0.001). K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval. (From Wallentin L, Becker R, Budaj A, et al: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045, 2009.) 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin et al. NEJM 2009;361:1045-57

15% RRR

Medical therapy (advanced) 2nd antiplatelet (ADP-receptor antagonist) Prasugrel, Clopidogrel, Ticagrelor Anticoagulant therapy Unfractionated heparin (4000-5000 units) I.V. Glycoprotein IIb/IIIa inhibitors, I.V. (provisional) Tirofiban (Aggrastat) Eptifibatide (Integrilin) Bivalirudin (in patients undergoing PPCI) Low-molecular weight heparin (LMWH) – for patients not managed by PPCI / thrombolysis Enoxaparin, Fondaparinux

TIMI risk score for STEMI TIMI risk score for STEMI predicting 30-day mortality. h/o = history of; HTN = hypertension; LBBB = left bundle branch block; STE = ST-segment elevation. (From Morrow DA, Antman EM, Charlesworth A, et al: The TIMI risk score for ST elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An InTIME II substudy. Circulation 102:2031, 2000.)

MI complications: Heart Failure Dilation of the ventricle – “remodeling” Increased wall stress Reduced ejection fraction Reduced functional capacity Fluid overload (pulmonary congestion, peripheral edema, pleural effusion) Look for Mitral Regurgitation (MR) Therapy: ACE inhibitors, Beta blockers, spironolactone, diuretics, digoxin

Impact of left ventricular function on survival following MI Impact of left ventricular function on survival following MI. The curvilinear relationship between left ventricular ejection fraction (EF) for patients treated in the fibrinolytic era is shown. Among patients with a left ventricular EF below 40%, the rate of mortality is markedly increased at 6 months. Thus, interventions such as thrombolysis, aspirin, and ACE inhibitors should be of considerable benefit in patients with acute MI to minimize the amount of left ventricular damage and interrupt the neurohumoral activation seen with congestive heart failure. (Modified from Volpi A, De Vita C, Franzosi MG, et al: Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base. The Ad Hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico [GISSI]-2 Data Base. Circulation 88:416, 1993.) Volpi A. GISSI-2 database. Circulation 1993;88:416

MI complications: Arrhythmias Ventricular tachycardia / fibrillation Prompt DC shock Bradycardia: Sinus bradycardia , AV block – inferior MI Atropin, Dopamine, Pacemaker Tachycardia: Sinus tachycardia Atrial fibrillation Treat heart failure

MI complications: Pericarditis Acute post MI pericarditis Anti-inflammatory drugs, NSAID Dressler syndrome Anti-inflammatory drugs, steroids

Cardiac Rupture Syndrmes Complicating STEMI Ventricular Septal Rupture – VSD with Rt. To Lt. Shunt Free Wall Rupture – Tamponade with Shock Papillary Muscle Rupture – with Severe Mitral Regurgitation Cardiac rupture syndromes complicating STEMI. A, Anterior myocardial rupture in an acute infarct. B, Rupture of the ventricular septum. C, Complete rupture of a necrotic papillary muscle.   (From Schoen FJ: The heart. In Kumar V, Abbas AK, Fausto N [eds]: Robbins & Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, Saunders, 2010, pp 529-587.)

MI complications: Rupture Intra-aortic balloon pump (IABP) If tamponade – prompt pericardiocentesis Urgent surgery

Therapy on discharge Healthy life-style Aspirin 2nd antiplatelet ACE-inhibitor Beta-blocker Statin (high dose) Cardiac rehabilitation Risk factor control (smoking, diabetes, hypertension, obesity, hyperlipidemia, etc.)

Trends in in-hospital drug therapy over 10 years: following the guidlines Data from ACSIS: Acute Coronary Syndrome Israeli Survey

Trends in outcome over 10 years: Mortality and MACE Data from ACSIS: Acute Coronary Syndrome Israeli Survey

View of the Hadassah – Hebrew University Medical Center Thank you View of the Hadassah – Hebrew University Medical Center