1. Fredric Ginsberg, MD Assistant Professor of Medicine, Robert Wood Johnson Medical School University of Medicine and Dentistry of New Jersey Joseph E. Parrillo, MD Professor of Medicine, Robert Wood Johnson Medical School University of Medicine and Dentistry of New Jersey Head, Division of Cardiovascular Disease and Critical Care Medicine Director, Cooper Heart Institute Director, Cardiovascular and Critical Care Services Cooper University Hospital Camden, New Jersey SCCM Online Critical Care Course: Cardiogenic Shock, Acute Coronary Syndrome and Congestive Heart Failure

4. Evolution Of The Disease Frequently, shock develops after presentation for myocardial infarction. - SHOCK Registry • At presentation 25% in shock • Within 24 hours 75% (median delay = 7 hours) - GUSTO Trial • At presentation 11% in shock • After admission 89% SHOCK Registry, Circulation. 1995;91:873-81. GUSTO J Amer Coll Cardiol. 1995;26:668-74 . Cardiogenic Shock

5. Wall motion abnormality during occlusion Wall motion abnormality From Kloner RA. Am J Med. 1986;86:14. Gradual return of function (hours to days) Persistent wall motion abnormality (despite reperfusion and viable myocytes) Coronary occlusion Coronary reperfusion Return of function Clamp Schematic Diagram of Stunned Myocardium

6. Atherosclerotic narrowing Wall motion abnormality due to chronic ischemia without infarction Wall motion abnormality From Kloner RA. Am J Med. 1986;86:14. Hibernating Myocardium

7. Pre-operative 8 Months Postoperative CONTROL LVEDV = 128 EF = 0.37 POST NTG LVEDV = 101 EF = 0.51 LVEDV = 104 EF = 0.76 Patient Coronary Bypass Graft to L.A.D. Single vessel disease - Occluded L.A.D. End-Diastole End-Systole From Rahimtoola SH, et al. Circ. 1992;65:225. Hibernating Myocardium

8. Cell death Significant residual stenosis Reperfusion Segments with myocardial stunning Segments with both stunning and hibernation Segments with hibernating myocardium Relief of ischemia Inotropic support No return of function Return of myocardial function Ischemic Myocardium

11. Overall 30-Day Survival in the Study Hochman JS, et al. N Engl J Med. 1999;341:625-34. Proportion Alive 0 Days after Randomization 0.6 0.2 0.0 0.8 Revascularization (n =152) Medical therapy (n =150) 1.0 0.4 5 10 15 20 25 30 Survival = 53% Survival = 44% p = 0.11 Early Revascularization in Acute Myocardial Infarction Complicated by Cardiogenic Shock

12. 46.7 50.3 54.3 56 63.1 66.4 0 20 40 60 80 100 % P = 0.11 P = 0.027 P < 0.03 30 days 6 months 1 year Revasc Med Rx SHOCK Trial Mortality

17. Thus, excess nitric oxide and peroxy nitrites may be a major contributor to cardiogenic shock complicating MI. The Overproduction of Nitric Oxide May Cause Both Myocardial Depression and Inappropriate Vasodilatation.

21. Plaque rupture Platelet adhesion Platelet activation Partially occlusive arterial thrombosis & unstable angina Microembolization & non-ST-segment elevation MI Totally occlusive arterial thrombosis & ST-segment elevation MI White HD. Am J Cardiol 1997;80 (4A):2B-10B. Pathogenesis of Acute Coronary Syndromes

22. UA/NSTEMI: Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet-dominated) Plaque core STEMI: Occlusive thrombus (platelets, red blood cells, and fibrin) Intra-plaque thrombus (platelet-dominated) Plaque core SUDDEN DEATH UA = Unstable Angina NSTEMI = Non-ST-segment Elevation Myocardial Infarction STEMI = ST-segment Elevation Myocardial Infarction Structure of Thrombus Following Plaque Disruption White HD. Am J Cardiol 1997;80 (4A):2B-10B.

23. Therapeutic goal: rapidly break apart fibrin mesh to quickly restore blood flow ST-segment elevation MI Non-ST Elevation ACS* Non-ST Elevation MI + T roponin or + CK-MB Consider fibrinolytic therapy, if indicated, or primary percutaneous coronary intervention (PCI) Therapeutic goal: prevent progression to complete occlusion of coronary artery and resultant MI or death Consider GP IIb-IIIa inhibitor + aspirin + heparin before early diagnostic catheterization &/or Braunwald E, et al. 2002. http://www.acc.org/clinical/guidelines/unstable/unstable.pdf . Diagnostic Algorithm for Acute Coronary Syndrome Management

24. 0 3 6 9 12 Probability of Death or MI Placebo Aspirin 75 mg Risk ratio 0.52 95% CL 0.37 - 0.72 Risk of MI and Death During Treatment with Low-Dose Aspirin and IV Heparin in Men with Unstable CAD Wallentin LC, et al. J Am Coll Cardiol, 1991;18:1587-93. Months 0.00 0.05 0.10 0.15 0.20 0.25

25. Trial: FRIC (Dalteparin; n = 1,482) FRAXIS (nadroparin; n = 2,357) ESSENCE (enoxaparin; n = 3,171) TIMI 11B (enoxaparin; n = 3,910) .75 1.0 1.5     (p= 0.032) (p= 0.029) LMWH Better UFH Better 6 14 14 14 Day: Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Low Molecular Weight Heparin (LMWH) vs. Unfractionated Haparin (UFH) in Non-ST elevation ACS: Effect on Death, MI, Recurrent Ischemia

26. 0 2 4 6 8 10 12 14 Death, MI, or Stroke Clopidogrel + ASA 3 6 9 Placebo + ASA Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 % N Engl J Med. 2001;345:494-502. Effects of Clopidogrel in Addition to Aspirin in Patients with ACS without ST-Segment Elevation

27. 15.7 5.6 17.9 11.7 12.8 14.2 3.8 12.9 10.3 11.8 0 5 10 15 20 Primary Endpoint % Placebo GP IIb/IIIa PURSUIT 30 days PRISM 48 hrs PRISM PLUS 7 days P = 0.04 P = 0.01 P = 0.004 PARAGON A 30 days P = 0.48 PARAGON B 30 days P = 0.33 Platelet Glycoprotein IIb/IIIa Inhibition for Non-ST elevation ACS Primary Endpoint Results from the 5 Major Trials

28. Hospital Care Anti-Thrombotic Therapy Immediate aspirin Clopidogrel, if aspirin contraindicated Aspirin + clopidogrel for up to one month, if medical therapy or PCI is planned Heparin (IV unfractionated, LMW) with antiplatelet agents listed above Enoxaparin preferred over UFH unless CABG is planned within 24 hours Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf I IIa IIb III

29. * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI Guidelines do not specify initial approach to using clopidogrel when coronary anatomy is unknown Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Hospital Care Clopidogrel Therapy Aspirin + clopidogrel, for up to 1 month * Aspirin + clopidogrel, for up to 9 months * Withhold clopidogrel for 5 - 7 days for CABG I IIa IIb III

30. * High-risk: Age >75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST  ; VT; positive cardiac markers Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Hospital Care Platelet GP IIb/IIIa Inhibitors (1) Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI planned Eptifibatide or tirofiban + ASA/Heparin for high-risk * patients in whom early cath/PCI is not planned Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is planned I IIa IIb III

31. Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Hospital Care Platelet GP IIb/IIIa Inhibitors (2) Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned I IIa IIb III

32. Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Hospital Care Anti-ischemic Therapy (1)  -blocker (IV  oral) if not contraindicated Non-dihydropyridine Ca2+ antagonist if  -blocker contraindicated and no LV dysfunction, for recurrent ischemia ACE inhibitor if  BP persists with NTG+  -blocker, for pts with CHF or diabetes I IIa IIb III

33. Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Hospital Care Anti-ischemic Therapy (2) ACE inhibitor for all ACS pts Extended-release Ca2+ blocker instead of  -blocker Immediate-release Ca2+ blocker with  -blocker Long-acting Ca2+ blocker for recurrent ischemia, if no contraindications and NTG +  -blocker used fully I IIa IIb III

34. 30 60 90 120 150 180 T-wave inversion 3.4% ST-segment elevation 6.8% ST-segment depression 8.9% Days from randomization % Cumulative Mortality at 6 Months Savonitto S. J Am Med Assoc. 1999; 281: 707-711. ST-segment Depression Predicts Higher Risk of Mortality in ACS 10% 8% 6% 4% 2%

38. Death/MI/ACS Rehosp (%) TIMI Risk Score CONS % of Pts: 25% 60% 15% INV OR = 0.75 CI (0.57, 1.00) OR = 0.55 CI (0.33, 0.91) TIMI UA Risk Score: Primary Endpoint at 6 months

39. Cannon. J Invas Cardiol. 2003;15:22B. Troponin and ST-Segment Shift Predict Benefit of Invasive Treatment Strategy

42. Recurrent Symptoms/ischemia Heart failure Serious arrhythmia Patient stabilizes EF  .40 Stress Test Not low risk Follow on Medical Rx Evaluate LV function EF < .40 Low risk Early medical management Immediate angiography Braunwald E, et al. 2002. http://www.acc.org/clinical/guidelines/unstable/unstable.pdf . Ongoing Evaluation in an Early Conservative Strategy

43. ST  , positive cardiac markers, deep T-wave inversion, transient ST  , or recurrent ischemia Aspirin, Beta Blockers, Nitrates, Antithrombin regimen, GP IIb-IIIa inhibitor, Monitoring (rhythm and ischemia) Immediate angiography Recurrent symptoms/ischemia Heart failure Serious arrhythmia Evaluate LV Function EF < .40 Not low risk Low risk Follow on Medical Rx Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf ACC/AHA Guidelines for Unstable Angina and Non-ST-Segment Elevation MI Acute Ischemia Pathway Early invasive strategy Early conservative strategy 12-24 hour angiography Patient stabilizes EF > .40 Stress Test

44. Class I indications for revascularization with PCI or CABG 1. CABG for  50% stenosis of the left main coronary artery 2. CABG for 3 vessel CAD 3. CABG for 2 vessel CAD including proximal LAD stenosis & EF < 50% 4. PCI or CABG for 1 or 2 vessel CAD, no proximal LAD, large area of viability, high-risk noninvasive test 5. PCI for patients with multivessel CAD, normal EF, no diabetes 6. IV platelet GP IIb/IIIa inhibitor in ACS patients undergoing PCI Braunwald. Circulation 2002; 106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation MI

45. Class IIa indications for revascularization with PCI or CABG 1. Repeat CABG for patients with multiple saphenous vein graft stenoses, especially if LAD graft 2. PCI for focal saphenous vein graft lesions or multiple lesions if poor surgical candidate 3. PCI or CABG for patients with 1 or 2 vessel CAD, not proximal LAD, but moderate area of viability and ischemia 4. PCI or CABG for patients with 1 vessel CAD with proximal LAD 5. CABG with Internal Mammary artery for patients with multivessel CAD and diabetes ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation MI Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf

46. Cardiac Catheterization Coronary Artery Disease Left Main Disease Discharge from Protocol NO CABG 1 or 2 Vessel Disease PCI or CABG, if eligible 3 Vessel Disease or 2 Vessel Disease with proximal LAD involvement Left Ventricular Dysfunction or Treated Diabetes CABG PCI or CABG YES NO NO YES Smith et al. ACC/AHA PCI Guidelines. J Am Coll Cardiol 2001:2239-lxvi. Recommendations for Revascularization

47. Braunwald E, et al. Circ. 2002;106:1893. * Recurrent ischemia; Trop; ST; LV failure/dysf.; hemodynamic instability; VT; prior CABG  Enoxeparin. Preferred to UFH (IIa)  If coronary arteriography >24 hours ACC/AHA REVISED GUIDELINES UA/NSTEMI High Risk * ASA, Heparin/ Enox. ,   block., Nitrates, Clopidogrel  RISK STRATIFY Low Risk

48. Braunwald E, et al. Circ. 2002;106:1893. ACC/AHA REVISED GUIDELINES LMCD, 3VD+LV Dys., or Diab. Mell. CABG High Risk Cor. Arteriography 1 or 2VD, Suitable for PCI Normal Clopidogrel, IIb/IIIa inhib. Consider Alternative Diagnosis Discharge on ASA, Clopidogrel, Statin, ACEI PCI

49. Braunwald. Circulation 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf Discharge/Post-discharge Medications ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel, for up to 9 months  -blocker, if not contraindicated Lipid  agents (statins) + diet ACE Inhibitor: CHF, EF < 40%, DM, or HTN I IIa IIb III

50. 0 3 18 21 24 27 30 6 9 12 15 % with Event Months of follow up Pravastatin 40 mg (26.3%) Atorvastatin 80 mg (22.4%) 16% RR ( P = 0.005) 30 25 20 15 10 5 0 All-Cause Death or Major Cardiovascular Events in All Randomized Subjects Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.

51. 2-Year Event Rates RR Atorva 80 Prava 40 28% 2.2% 3.2% 30% 1.1% 1.4% 13% 6.6% 7.4% 18% 8.3% 10.0% 14% 16.3% 18.8% 29% 3.8% 5.1% 14% 19.7% 22.3% 0.5 1.0 1.5 All-cause Mortality Death or MI MI Revasc >30 d UA Requiring Hospitalization 0.75 1.25 Atorvastatin 80 mg Better Pravastatin 40 mg Better Death/MI/Urgent Revascularization Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. Reductions in Major Cardiac End Points CHD-related Death

52. Risk Factor Modification Smoking Cessation Counseling Dietary Counseling and Modification Cardiac Rehabilitation Referral HTN Control (BP <130/85 mm Hg) Tight Glycemic Control in Diabetics Braunwald. Circulation. 2002;106:1893-2000. www.acc.org/clinical/guidelines/unstable/unstable.pdf I IIa IIb III

54. Myocardial injury to the heart (CAD, HTN, CMP, valvular disease) Morbidity and mortality Arrhythmias Pump failure Peripheral vasoconstriction Hemodynamic alterations Heart failure symptoms Remodeling and progressive worsening of LV function Initial fall in LV performance,  wall stress Activation of RAS and SNS Fibrosis, apoptosis, hypertrophy, cellular/ molecular alterations, myotoxicity F atigue A ctivity altered C hest congestion E dema S hortness of breath Neurohormonal Activation in Heart Failure RAS, renin-angiotensin system; SNS, sympathetic nervous system .

55. LV Remodeling Post Anteroseptal MI 1 week 3 months EDV 137 mL ESV 80 mL EF 41% EDV 189 mL ESV 146 mL EF 23% Apical 4 Chamber View

63. P = .0014 All-cause Mortality % Survival Carvedilol Placebo 100 90 80 60 70 0 Packer M et al. N Engl J Med. 2001;344:1651–1658. Coreg (carvedilol) Prescribing Information. GlaxoSmithKline, Research Triangle Park, NC. Mar 2003. Risk reduction  35% (19%, 48%) n = 1156 n = 1133 Mortality rates: Placebo 19.7%; Carvedilol 12.8% COPERNICUS 0 3 6 9 12 15 18 21 Months

66. Angiotensin Receptor Blockers in CHF No increased mortality w/ beta-blocker Small decrease in mortality when added to ACE-I Candesartan CHARM 2003 33% decreased mortal if not on ACE-I 19.9 vs. 19.4 (p = NS) < 40% Valsartan ValHeft 2001 17.7 vs. 15.9 (p = NS) < 40% Losartan vs. captopril ELITE II 2000 6.1 vs. 3.7 (p = NS) Avg 27% Candesartan vs enalapril RESOLVD 1999 Notes Mortality vs. ACE-I Baseline EF Drugs Trial

68. Aldosterone Blockers in CHF 5.5% Reduced from 14.6% to 8.5% (p = .008) ACE-I and beta-blocker Post-MI w/ EF < 40% or diabetes eplerenone EPHESUS 2003 2% Reduced from 46.3% to 35% (p < .001) ACE-I, no beta-blocker Class III and IV CHF spironolactone RALES 1999 Hyper- kalemia Mortality vs. placebo Added therapy Patients Drug Study

73. A-Heft: Kaplan-Meier Estimates of Overall Survival