Acute Coronary Syndrome #2 July 26, 2013

Class of Recommendation Level of Evidence A Class I: Benefit >>> Risk Class IIa: Benefit >> Risk Class IIb: Benefit ≥ Risk Class III: Risk ≥ Benefit Data from randomized clinical trials or meta-analysis Procedure or treatment should be performed B It is reasonable to perform procedure or treatment Data from single randomized trial or nonrandomized studies It is reasonable to consider procedure or treatment C Consensus of opinion of experts, case studies or standard of care Procedure or treatment should not be performed

Percutaneous Coronary Intervention (PCI) Facilitated PCI: Strategy of full or half dose fibrinolytic therapy with or without IIb/IIIa receptor antagonist with immediate transfer or planned PCI within 90 to 120 minutes. Rescue PCI: Transfer for PCI of patients who failed reperfusion with fibrinolytic therapy. 2013 ACCF/AHA Guideline for STEMI, JACC 2013:61:

Fibrinolysis Primary PCI Coronary Angioplasty VS Fibrinolytic Therapy in Acute Myocardial Infarction Fibrinolysis Door-to-Needle or FMC to Needle < 30 mins Not PCI capable EMS Transport PCI capable Primary PCI Door-to-Balloon or FMC to Balloon ≤ 90 mins

Door-to-Balloon or FMC to Balloon ≤ 120 mins Coronary Angioplasty VS Fibrinolytic Therapy in Acute Myocardial Infarction DIDO 30 mins Not PCI capable EMS Transport 2013 STEMI Guideline PCI capable PCI Door-to-Balloon or FMC to Balloon ≤ 120 mins

PCI + Thrombolytic Therapy IIa IIb III 2007 ACC/AHA STEMI Guideline B A planned strategy using full dose fibrinolytic therapy followed by immediate PCI is not recommended and may be harmful.

Use of IIb/IIIa antagonists in STEMI Abciximab (Reopro) Eptifibatide (Integrilin) Tirofiban (Aggrastat)

IIb/IIIa Antagonists in STEMI 2009 ACC/AHA STEMI Guideline Facilitated PCI B The usefulness of IIb/IIIa receptor antagonists (as part of a preparatory pharmacologic strategy for STEMI patients prior to arrival in cardiac catheterization lab for angiography and PCI) is uncertain.

Use of Thienopyridines in STEMI Also called P2Y12 receptor inhibitors Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta)

Use of Thienopyridines in STEMI IIa IIb III C Clopidogrel during PCI 2007 STEMI guidelines 600 mg loading dose 2009 STEMI guidelines at least 300 to 600 mg Prasugrel during PCI 2009 STEMI guidelines 60 mg loading dose Ticagrelor during PCI 180 mg loading dose once followed by 90 mg bid. ASA 325 mg then <100 mg maintenance dose

Use of Thienopyridines in STEMI IIa IIb III C Clopidogrel with fibrinolytic therapy 2013 STEMI guidelines ≤ 75 y = 300 mg loading dose > 75 y = no loading dose

IIb/IIIa Antagonists in STEMI LOE: I IIa IIb III A: Abciximab 2007 ACC/AHA STEMI Guideline AB B: Tirofiban Integrilin It is reasonable to start treatment with IIb/IIIa receptor antagonist at the time of primary PCI (with or without stenting) in selected patients with STEMI.

MKSAP Item #82 A 55 year old man is evaluated for a 2-month history of dyspnea on exertion without chest pain. Medical history is significant for type 2 diabetes mellitus, hypertension and hyperlipidemia. Medications are metformin, lisinopril, pravastatin and aspirin. On physical exam, BP is 110/75 mm Hg and pulse rate is 60/min. BMI is 35. Jugular venous distention is noted, and trace lower extremity edema is present.

MKSAP Item #82 The point of maximal impulse is normal. Cardiac exam reveals a regular rate and rhythm and the chest is clear to auscultation. Laboratory studies show a serum B-type naturetic peptide level of 110 pg/mL. The EKG is shown. Echocardiogram shows inferior wall hypokinesis and ejection fraction of 35%.

MKSAP Item #82

MKSAP Item #82 Which of the following is the most appropriate diagnostic test to perform next? Adenosine thallium stress test Cardiac magnetic resonance imaging Cardiopulmonary exercise test Coronary angiography

MKSAP Item #64 A 64-year old woman is evaluated in the ED for chest pain and SOB. The chest pain began earlier in the day after she received news that her younger sister had died in a motor vehicle accident. She reports no similar episodes of chest pain before today. She takes no meds. On PE, temperature is 37.30 C, BP is 150/80 mm Hg, pulse rate is 90/min, and respiration rate is 11/min. BMI is 24. A normal carotid upstroke without carotid bruits is noted, jugular venous pulsations are normal, and normal S1 and S2 are heard without murmurs.

MKSAP Item #64 Serum troponin level is 1.4 ng/mL. EKG displays sinus rhythm at 90/min, 1-mm ST elevation in leads V1 through V4, and no Q waves. Echo shows reduced wall motion of the anterior and apical portion of the heart, hyperdynamic wall motion of the basal segments, no significant valvular disease, and no pericardial effusion. She undergoes emergent coronary angiography, which shows normal coronary arteries. Ventriculography shows no movement of the apical portion of the heart and hyperdynamic wall motion of the basal segments of the heart.

MKSAP Item #64 Which of the following is the most likely diagnosis? Non-ST elevation MI Pericarditis ST elevation MI Stress cardiomyopathy

Item 68 A 56-year old man is admitted to the hospital with new onset substernal chest pressure. Medical history is remarkable for hyperlipidemia. He is a cigarette smoker. His medications are aspirin and atorvastatin; upon admission to the hospital, he began receiving metoprolol, clopidogrel and IV heparin. On PE, the patient is afebrile, BP is 132/78 mm HG, pulse rate is 82/min and regular, and respiration rate is 14/min. No jugular venous distention is note, the lungs are clear to auscultation, no murmur or gallop is heard and no peripheral edema is noted.

Item 68 (con’t) On admission, cardiac troponin I level was 1.2 ng/mL; on hospital day 2, it peaks at 8.4 ng/mL. ECG on arrival to the ED demonstrated nonspecific ST-T wave abnormality, but no ST segment elevation or depression. Cardiac catheterization demonstrates overall preserved LV systolic function with diffuse severe disease of the distal portion of all three major epicardial vessels. No catheterization based intervention is performed.

Item 68 (con’t) Which of the following is the most appropriate management of this patient’s clopidogrel therapy? Stop clopidogrel Continue clopidogrel for 2 weeks Continue clopidogrel therapy for 1 year Continue clopidogrel therapy lifelong.

Hospitalizations in the US due to ACS Acute Coronary Syndromes 1.57 Million Hospital Admissions 79% 21% UA/NSTEMI STEMI Approximately 2.3 million Americans will present to the emergency department with chest pain due to acute coronary syndrome.[1] Of these patients, twice as many (1.43 million) will be admitted and diagnosed with unstable angina (UA) or non–ST-segment elevation myocardial infarction (NSTEMI; also known as non–Q-wave MI) compared with 829,000 patients who will be diagnosed with ST-segment elevation MI (STEMI; also known as Q-wave MI).[1] According to the American Heart Association, 1.1 million new or recurrent coronary attacks (defined as MI or coronary heart disease) will occur this year.[2] Of these cases, 650,000 will be first cases and 450,000 will be recurrent cases. Additionally, about 150,000 new cases of UA will be diagnosed.[2] National Center for Health Statistics. 1999 National Hospital Discharge Survey: Annual Summary with Detailed Diagnosis and Procedure Data. Hyattsville, Maryland: US Dept of Health and Human Services; 2001: Series 13, No. 151. American Heart Association. 2002 Heart and Stroke Statistical Update. 2001. 0.33 million admissions 1.24 million admissions 0.57 million NSTEMI 0.67 million UA Heart Disease and Stroke Statistics 2007 Update Circulation 2007;115:69-171 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 23

Atherosclerotic plaque Acute Coronary Syndromes Pathophysiology Large Fissure Small Fissure Mural thrombus (unstable angina/ non-ST elevation MI) Occlusive thrombus (ST Elevation MI) Thrombus Lipid Pool Macrophages Stress, tensile, internal Shear forces, external Atherosclerotic plaque Fissure Plaque rupture Fuster V et al. NEJM. 1992; 326: 310-318. Davies MJ et al. Circulation. 1990; 82 (Suppl II): II-38, II-46.

Non-ST elevation - coronary artery is not completely occluded Myocardial Ischemia Blood Supply Oxygen Demand TIMI 1 or 2 Flow Heart Rate Blood Pressure Inotropicity Non-ST elevation - coronary artery is not completely occluded

Mortality Rates According to Level of Cardiac Troponin Troponin Levels Predict Risk of Mortality in ACS at 42 days in TIMI III B 8 7.5 7 6.0 6 5 Mortality at 42 days (Percentage of Patients) 4 3.7 3.4 3 2 1.7 1.0 1 831 174 148 134 50 67 0-0.4 0.4-<1.0 1.0 -<2.0 2.0 -<5.0 5.0 -<9 >9.0 Cardiac Troponin (ng/ml) Circulation 2011;123:e451 NEJM 1996;335:1342-9

Non-ST Elevation MI/Unstable Angina

Non-ST Elevation MI/Unstable Angina

Diagnostic and Therapeutic Pathways in Patients With and Without Persistent ST-Segment Elevation Acute Coronary Syndrome ECG Persistent ST-segment elevation ACS, No ST-segment elevation Thrombolysis, PCI Aspirin, clopidogrel, UFH or LMWH, b-blockers, nitrates Hamm CW et al. Lancet. 2001;358:1533-1538. 2002 ACC/AHA UA/NSTEMI Guideline Update. Available at: www.acc.org

Myocardial Ischemia Blood Supply Oxygen Demand TIMI 1 or 2 Flow Heart Rate Blood Pressure Inotropicity Non-ST elevation ACS indicates that there is coronary blood flow, but not adequate to supply enough oxygen to the myocardium

Coronary angiography only if Continuing ischemia or (+) Stress test Diagnostic and Therapeutic Pathways in Patients With non-ST Segment Elevation UA/NSTEMI ASA/Clopidogrel/Heparin Nitrates/Beta blockers Conservative Therapy Aggressive Therapy Low risk High risk Medical Therapy Only Stress Test Coronary angiography within 24-48 hours Coronary angiography only if Continuing ischemia or (+) Stress test 2007 ACC/AHA Guidelines for the Management of Patients with Unstable angina/NSTEMI. www.acc.org

NSTEMI/Unstable Angina High Risk Markers (Invasive Strategy) Elevated troponins Recurrent angina/ischemia at rest or with low level activities New or presumably new ST segment depression Recurrent angina/ischemia with CHF, S3 gallop, rales, MR High risk findings on noninvasive stress testing Depressed LVF (EF <0.40) Hemodynamic instability Sustained VT PCI within 6 months Prior CABG High GRACE or TIMI Risk Score Low Risk (Conservative Strategy) 2011 ACCF/AHA UA/Non-STEMI Guidelines. Circulation 2011;123 e458

TIMI Risk Score NSTEMI/Unstable Angina 7 Variables (One Point Each) Age 65 years or older At least 3 risk factors for CAD Prior coronary stenosis of 50% or more ST segment deviation on ECG presentation At least 2 anginal events in prior 24 hours Use of aspirin in prior 7 days Elevated serum cardiac biomarkers JAMA 2000;284:835-842

TIMI Risk Score TIMI Risk Score JAMA 2000;284:835-842 All Cause Mortality, New or Recurrent MI or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 days after Randomization (%) TIMI Risk Score 0-1 4.7% 2 8.3% 3 13.2% 4 19.9% 5 26.2% 6-7 40.9% JAMA 2000;284:835-842

GRACE Prediction Score Card Medical History Age in years (0-100 points) History of congestive heart failure (24 points) History of myocardial infarction (12 points) Findings at initial hospital presentation Resting heart rate (0-43 points) Systolic blood pressure (0-24 points) ST depression (11 points) Findings during hospitalization Initial serum creatinine (1 to 20 points) Elevated cardiac enzymes (15 points) No in-hospital percutaneous coronary intervention (14 points) JAMA 2004:291;2727-33

Medical History Age in years Points History of CHF 24 History of MI 12 ≤29 30-39 40-49 18 50-59 36 60-69 55 70-75 73 80-89 91 ≥90 100 JAMA 2004:291;2727-33

Findings at Initial Hospital Presentation 4. Resting HR BPM Points ≤49.9 50-69.9 3 70-89.9 9 90-109.9 14 110-149.9 23 150-199.9 35 ≥200 43 5. Systolic BP (mm Hg) ≤79.9 43 80-99.9 22 100-119.9 18 120-139.9 14 140-159.9 10 160-199.9 4 ≥200 4 6. ST Segment Depression 11

Findings During Hospitalization 7. Initial Serum Creatinine Points 0-0.39 1 0.4-0.79 3 0.8-1.19 5 1.2-1.59 7 1.6-1.99 9 2.3 -3.99 15 ≥4 20 8. Elevated Cardiac Enzyme 15 9. No In-hospital PCI 14 JAMA 2004:291;2727-33

GRACE Prediction Score Card Points JAMA 2004:291;2727-33 1. _______ 0.50 2. _______ 3. _______ 0.40 4. _______ 5. _______ 0.30 Mortality Risk Probability (All Cause Mortality 6 Mos) 6. _______ 0.20 7. _______ 8. _______ 0.10 9. _______ Total Score _____ 70 90 110 130 150 170 190 210 Mortality Risk from Plot __________ Total Risk Score = No. of Points

NSTEMI/Unstable Angina High Risk Markers (Invasive Strategy) Elevated troponins Recurrent angina/ischemia at rest or with low level activities New or presumably new ST segment depression Recurrent angina/ischemia with CHF, S3 gallop, rales, MR High risk findings on noninvasive stress testing Depressed LVF (EF <0.40) Hemodynamic instability Sustained VT PCI within 6 months Prior CABG High GRACE or TIMI Risk Score Low Risk (Conservative Strategy) 2011 ACCF/AHA UA/Non-STEMI Guidelines. Circulation 2011;123 e458

STRIVE TM

Invasive Strategy for UA/NSTEMI ASA (If ASA intolerant Clopidogrel) Invasive Strategy Anticoagulant therapy (Enoxaparin or UFH Bivaluridin or Fondaparinux) Prior to Angiography Initiate one or both of the following Clopidogrel /IV IIb/IIIa inhibitor Give both if there is Delay to Angiography, High Risk Features, Early recurrent ischemic discomfort

Conservative Strategy for UA/NSTEMI ASA (If ASA intolerant Clopidogrel) Conservative Strategy Anticoagulant therapy (Enoxaparin or UFH or Fondaparinux but enoxaparin and fondaparinus are preferable) Initiate Clopidogrel Consider adding IV eptifibatide or tirofiban Continue ASA indefinitely Continue clopidogrel >1 year D/C IIb/IIIA if started D/C anticoagulant therapy May need angio if LVEF <40%, + Stress test or there is Ischemia (Induced or Spontaneous)

Acute Coronary Syndrome Non-ST Segment Elevation Aspirin Clopidogrel Heparin 2B/3A Antagonists Nitrates/Oxygen/Morphine Beta Blockers ACE Inhibitors/ARB’s Statins Aldosterone antagonist (EF <40%)

Medication/Intervention STEMI Non-STEMI/ Unstable Angina Medication/Intervention STEMI Aspirin Yes Yes Clopidogrel Yes Yes Heparin Yes Yes 10 PCI – No tPa (thrombolytic agent) No No PCI – Yes PCI – Yes 10 PCI – Yes IIb/IIIa antagonists No PCI – High Risk only -Yes No PCI – No Beta Blockers Yes Yes ACE Inhibitors/ARB Yes Yes LV Dysfunction Aldosterone Antagonists Yes Yes Statins Yes Yes