1. ACLS 2009 Acute Coronary Syndromes M. LaCombe MDFMR June 3, 2009

2. Our first case: Chief Complaint: 30 minutes of squeezing substernal chest pain History of Present Illness: A 60-year-old hypertensive diabetic male presents to the emergency room (ER) with 30 minutes of squeezing substernal chest pain, relieved by sublingual nitroglycerin and nasal oxygen. Risk factors: positive for hypertension and diabetes mellitus

3. Physical Findings: Age: 60 Gender: Male Weight: 60 kg Blood Pressure: 130/76 mm Hg Pulse: 86 bpm Head and Neck: Normal jugular venous pressure Chest and Lungs: clear Cardiac Exam: Regular rhythm, no murmurs, gallops Extremities: 2+ symmetric

4. EKG:

5. Labs: troponin is 4.2 (what other labs are absolutely essential in this case?)

6. Stool for occult blood renal function studies

7. How will you treat this patient?

12. Copyright ©2005 American Heart Association Circulation 2005;112:IV-89-IV-110 Acute Coronary Syndromes Algorithm

15. ACS Risk Guided Algorithm Definite ACS Possible ACS (–) ECG; Normal biomarkers Observe; repeat ECG, markers at 4-8 h No recurrent pain; (–) follow-up studies Recurrent pain; (+) follow-up studies Stress test;  LV function if ischemia (–) test: outpatient follow-up (+) test Use 2007 NSTE ACS Guidelines ST  Use 2004 Updated MI Guidelines No ST  ST-T  ’s, def. pain,  markers Symptoms Suggestive of ACS

16. Applying Classification of Recommendations Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL should is recommended is indicated is useful/effective/ beneficial is reasonable can be useful/effective/ beneficial is probably recommended or indicated may/might be considered may/might be reasonable usefulness/effectiveness is unknown /unclear/uncertain or not well established is not recommended is not indicated should not is not useful/effective/beneficial may be harmful

17. Applying Classification of Recommendations and Level of Evidence Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Level A: Recommendation based on evidence from multiple randomized trials or meta-analyses Multiple (3-5) population risk strata evaluated; General consistency of direction and magnitude of effect Level B: Recommendation based on evidence from a single randomized trial or non-randomized studies Limited (2-3) population risk strata evaluated Level C: Recommendation based on expert opinion, case studies, or standard-of-care Very limited (1-2) population risk strata evaluated

18. Acute Evaluation of ACS ST-segment Elevation Chest pain or Short of Breath NSTEMI ST-segment Depression – + + Presentation ECG Diagnosis Normal Markers STEMI – + Rule-Out Adapted from: Anderson JL. J Am Coll Cardiol 2007;50:e1-157

23. Alert: Avoid beta blockers in ACS if there is impending cardiogenic shock! Cardiogenic Shock: Current Concepts and Improving Outcomes Reynolds HR, Hochman JS Circulation. 2008;117:686-697 Cardiogenic Shock: Basics and Clinical Considerations Gowda RM, Fox JT, Khan IA Int J Cardiol. 2008;123:221-228

24. Cardiogenic shock (CS) is defined as a state of tissue hypoperfusion resulting from cardiac failure. Hypoperfusion may manifest as systemic hypotension, peripheral vasoconstriction and diminished pulses, decreased urine output, decreased mental status, or significantly reduced cardiac indices (cardiac index) despite correction of preload. CS occurs in 5% to 10% of patients hospitalized with MI (ST-segment elevated MI) and is a common cause of death in this group. An unknown additional number of prehospital patients die from CS, making the exact incidence uncertain. Risk factors for development of post-MI CS include older age, anterior location of MI, hypertension, diabetes, multivessel occlusions, left bundle branch block, and prior history of cardiac disease or heart failure. Tachycardia and/or hypotension at admission predict CS in patients with MI.

27. Select Management Strategy: Initial Invasive Versus Initial Conservative Strategy Major Changes New Trial Data

28. Selection of Initial Treatment Strategy: Initial Invasive Versus Conservative Strategy Invasive Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New/presumably new ST-segment depression Signs/symptoms of heart failure or new/worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 months Prior CABG High risk score (e.g., TIMI, GRACE) Reduced left ventricular function (LVEF < 40%) Conservative Low risk score (e.g., TIMI, GRACE) Patient/physician presence in the absence of high-risk features

29. Risk Scores Antman EM, et al. JAMA 2000;284:835–42. Eagle KA, et al. JAMA 2004;291:2727–33. GRACE = Global Registry of Acute Coronary Events; TIMI = Thrombolysis in Myocardial Infarction. TIMI GRACE History Age Hypertension Diabetes Smoking ↑ Cholesterol Family history History of CAD Age Presentation Severe angina Aspirin within 7 days Elevated markers ST-segment deviation Heart rate Systolic BP Elevated creatinine Heart failure Cardiac arrest Elevated markers ST-segment deviation

30. Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy Proceed to Diagnostic Angiography ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) Diagnosis of UA/NSTEMI is Likely or Definite Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) Select Management Strategy Proceed with an Initial Conservative Strategy Anderson JL, et al. J Am Coll Cardiol . 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence. Prior to Angiography Init at least one (Class I, LOE: A) or both (Class IIa, LOE: B) of the following: Clopidogrel IV GP IIb/IIIa inhibitor Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort

35. GP IIb/IIIa Inhibition for Non – ST-Elevation ACS 30-Day Death or Nonfatal MI Risk Ratio and 95% CI Placebo Better GP IIb/IIIa Inhibitor Better Trial Pooled 11.5% Placebo GP IIb/IIIa Inhibitor 10.7% 29,855 n 0.92 (0.86, 0.995) P =.037 PRISM-PLUS 11.9% 10.2% 1,915 PURSUIT 15.7% 14.2% 9,461 PARAGON A 11.7% 11.3% 2,282 7.1% PRISM 5.8% 3,232 0.5 1.0 1.5 PARAGON B 11.4% 10.5% 5,165 GUSTO-IV ACS 8.0% 8.7% 7,800 Boersma E, et al. Lancet. 2002;359:189-198. CI = confidence interval.

36. Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials Newby KL, et al. Circulation . 2001;103:2891-2896. TnT-Negative TnT-Positive PARAGON-B PRISM CAPTURE Combined 0.125 1 2 0.5 0.125 1 2 0.5 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse

37. ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin levels (>0.03 µg/L) ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2. Adapted with permission from Kastrati A, et al. JAMA . 2006;295:1531-1538. 0 5 10 15 20 25 30 Days After Randomization Cumulative Rate of Primary End Point, % Placebo Group (n=1010) Abciximab Group (n=1012) Troponin >0.03 µg/L Log-Rank P =.02 Troponin < 0.03 µg/L Log-Rank P =.98 20 15 10 5 0

41. Init clopidogrel (Class I, LOE: A) Consider adding IV eptifibatide or tirofiban (Class IIb, LOE: B) Conservative Strategy Init anticoagulant therapy (Class I, LOE: A): Acceptable options: enoxaparin or UFH (Class I, LOE: A) or fondaparinux (Class I, LOE: B), but enoxaparin or fondaparinux are preferable (Class IIa, LOE: B) Select Management Strategy ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) Diagnosis of UA/NSTEMI is Likely or Definite Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy Proceed with Invasive Strategy (Continued) Anderson JL, et al. J Am Coll Cardiol . 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.

42. Any subsequent events necessitating angiography? EF greater than 40% Evaluate LVEF Low Risk Cont ASA (Class I, LOE A) Cont clopidogrel (Class I, LOE A) and ideally up to 1 yr (Class I, LOE B) DC IV GP IIb/IIIa if started previously (Class I, LOE A) DC ACT (Class I, LOE A) (Class I, LOE: B) Proceed to Dx Angiography Yes EF 40% or less Stress Test (Class I, LOE: A) No Not Low Risk (Class IIa, LOE: B) Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy (Continued) Anderson JL, et al. J Am Coll Cardiol . 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence. (Class I, LOE: A) (Class IIa, LOE: B) (Class I, LOE: B) (Class I, LOE: A)

48. Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI Medical Therapy without Stent Bare Metal Stent Group Drug Eluting Stent Group ASA 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 month and up to 1 year (Class I, LOE:B) Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B) Continue with dual antiplatelet therapy as above Yes No Indication for Anticoagulation? ASA 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I, LOE: B) ASA 162 to 325 mg/d for at least 3 to 6 months, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B) Anderson JL, et al. J Am Coll Cardiol 2007;50:e1 – e157, Figure 11. INR = international normalized ratio; LOE = level of evidence. UA/NSTEMI Patient Groups at Discharge New

56. Next Case: Chief Complaint: Subxiphoid burning sensation and dyspnea History of Present Illness: A 48-year-old female who smokes two packs per day presents with 1 hour of a subxiphoid burning sensation with dyspnea and diaphoresis, which are ongoing. She denies any prior cardiovascular or gastrointestinal history. Risk factor: positive family history of premature coronary artery disease

57. Age: 48 Gender: Female Blood Pressure: 170/95 mm Hg Pulse: 96 bpm Head and Neck: Jugular venous pressure, 10 Chest and Lungs: Clear Cardiac Exam: Regular rhythm, normal S 1 /S 2 ; S 4 present Extremities: 2+ pulses, no edema

58. Her EKG:

59. Copyright ©2005 American Heart Association Circulation 2005;112:IV-89-IV-110 Acute Coronary Syndromes Algorithm

63. ED Evaluation of Patients With STEMI 1. Airway, Breathing, Circulation (ABC) 2. Vital signs, general observation 3. Presence or absence of jugular venous distension 4. Pulmonary auscultation for rales 5. Cardiac auscultation for murmurs and gallops 6. Presence or absence of stroke 7. Presence or absence of pulses 8. Presence or absence of systemic hypoperfusion (cool, clammy, pale, ashen) Brief Physical Examination in the ED

64. ED Evaluation of Patients With STEMI Aortic dissection Pulmonary embolus Perforating ulcer Tension pneumothorax Boerhaave syndrome (esophageal rupture with mediastinitis) Differential Diagnosis of STEMI: Life-Threatening

65. ED Evaluation of Patients With STEMI Pericarditis Atypical angina Early repolarization Wolff-Parkinson-White syndrome Deeply inverted T-waves suggestive of a central nervous system lesion or apical hypertrophic cardiomyopathy LV hypertrophy with strain Brugada syndrome Myocarditis Hyperkalemia Bundle-branch blocks Vasospastic angina Hypertrophic cardiomyopathy Differential Diagnosis of STEMI: Other Cardiovascular and Nonischemic

66. Gastroesophageal reflux (GERD) and spasm Chest-wall pain Pleurisy Peptic ulcer disease Panic attack Cervical disc or neuropathic pain Biliary or pancreatic pain Somatization and psychogenic pain disorder ED Evaluation of Patients With STEMI Differential Diagnosis of STEMI: Other Noncardiac

67. Electrocardiogram Show 12-lead ECG results to emergency physician within 10 minutes of ED arrival in all patients with chest discomfort (or anginal equivalent) or other symptoms of STEMI. In patients with inferior STEMI, ECG leads should also be obtained to screen for right ventricular infarction.

68. Right Ventricular Infarction Clinical findings: Shock with clear lungs, elevated JVP Kussmaul sign Hemodynamics: Increased RA pressure (y descent) Square root sign in RV tracing ECG: ST elevation in R sided leads Echo: Depressed RV function Rx: Maintain RV preload Lower RV afterload (PA---PCW) Inotropic support Reperfusion V 4 R Modified from Wellens. N Engl J Med 1999;340:381.

69. Biomarkers of Cardiac Damage Cardiac-specific troponins should be used as the optimum biomarkers for the evaluation of patients with STEMI who have coexistent skeletal muscle injury. For patients with ST elevation on the 12-lead ECG and symptoms of STEMI, reperfusion therapy should be initiated as soon as possible and is not contingent on a biomarker assay.

70. Cardiac Biomarkers in STEMI 0 1 2 3 4 5 6 7 8 Cardiac troponin-no reperfusion Days After Onset of STEMI Multiples of the URL Upper reference limit 1 2 5 10 20 50 URL = 99th %tile of Reference Control Group 100 Cardiac troponin- reperfusion CKMB-no reperfusion CKMB- reperfusion Alpert et al. J Am Coll Cardiol 2000;36:959. Wu et al. Clin Chem 1999;45:1104.

71. STEMI ST-segment elevation or presumed new LBBB in 2 or more contiguous precordial or limb leads

75. Fibrinolysis In the absence of contraindications, fibrinolytic therapy should be administered to STEMI patients with symptom onset within the prior 12 hours. In the absence of contraindications, fibrinolytic therapy should be administered to STEMI patients with symptom onset within the prior 12 hours and new or presumably new left bundle branch block (LBBB).

76. Fibrinolysis In the absence of contraindications, it is reasonable to administer fibrinolytic therapy to STEMI patients with symptom onset within the prior 12 hours and 12-lead ECG findings consistent with a true posterior MI. In the absence of contraindications, it is reasonable to administer fibrinolytic therapy to patients with symptoms of STEMI beginning in the prior 12 to 24 hours who have continuing ischemic symptoms and ST elevation > 0.1 mV in ≥ 2 contiguous precordial leads or ≥ 2 adjacent limb leads.

77. Fibrinolysis Fibrinolytic therapy should not be administered to asymptomatic patients whose initial symptoms of STEMI began more than 24 hours earlier. Fibrinolytic therapy should not be administered to patients whose 12-lead ECG shows only ST-segment depression, except if a true posterior MI is suspected.

80. Thienopyridines In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days, and preferably for 7 days, unless the urgency for revascularization outweighs the risk of excessive bleeding. NOTE: Surgeons at MMC will take a patient to the OR for bypass even if given a loading dose of Plavix that day. This represents a change.

82. All-Cause Mortality Years Probability of Event ACE-I 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Flather MD, et al. Lancet . 2000;355:1575–1581 OR: 0.74 (0.66–0.83) ACE-I: 702/2995 (23.4%) Placebo: 866/2971 (29.1%) TRACE Echocardiographic EF  35% AIRE Clinical and/or radiographic signs of HF SAVE Radionuclide EF  40% 0 0.05 0.1 0.15 0.2 0.25 0.3 0 1 2 3 0.35 0.4 4 ACE-I Placebo

83. Last Case: A 58 y.o. man presents to the ER with a complaint of chest pain. His EKG and initial troponin are both normal. How will you proceed?

87. Then, use the medical literature:

88. Diamond and Forrester: New England Journal of Medicine 1979; 300 (24): 1350 300 (24): 1350- -1358

89. Diamond and Forrester: New England Journal of Medicine 1979; 300 (24): 1350 300 (24): 1350- -1358

91. Now, you need to use Bayes’ Theorem… that is of course unless you are like me and want a short-cut. Here’s a short cut: It’s called the Fagan nomogram:

93. … together with your pretest probability you have estimated for your patient. And the likelihood ratios… for mibis, the +LR is about 2.4 and the –LR is about .2

94. But look at the nomogram again! Are you convinced that stress testing is most helpful for the patient with intermediate pretest probability?

95. Remember, central to the ACS algorithm is the 12-lead EKG. Which of these are acute MI’s?

102. And which of these is V. Tach?

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