Pathology, Pathophysiology, and Epidemiology

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1 Non-ST-Segment Elevation Acute Coronary Syndrome (NSTE-ACS) Vincent J. Pompili, M.D., FACC Professor of Internal Medicine Director of Interventional Cardiology The Ohio State University Richard M. Ross Heart Hospital Pathology, Pathophysiology, and Epidemiology Non-ST-Segment Elevation Acute Coronary Syndrome The Vulnerable Plaque Pathology, Pathophysiology, and Epidemiology Risk and Risk Stratification Initial Therapies and Management Platelets and Anti-Platelet Therapies Anti-Thrombin Studies and Recommendations Early Invasive Strategy Peri- and Post-Discharge Medications and Management Thin, Vulnerable, Fibrous Cap Large Lipid Core Reproduced with permission from Falk E, et al. Circulation. 1998;92:

2 Ruptured Plaque with Occlusive Thrombus Formation Characteristics of Unstable and Stable Plaque Thrombus Formation Few SMCs Unstable Thin fibrous cap Inflammatory cells More SMCs Stable Thick fibrous cap Lack of inflammatory cells Eroded endothelium Activated macrophages Intact endothelium Foam cells Reproduced with permission from Falk E, et al. Circulation. 1998;92: Adapted with permission from Libby P. Circulation. 1995;91: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque Systemic and Focal Plaque Rupture by IVUS in ACS Patients Undergoing PCI 1 Analysis of 72 Arteries (n=24 TnI-positive ACS Patients) % Plaque rupture % 79. % 7.8 % 25 Plaque rupture at site of culprit lesion Plaque rupture elsewhere than site of culprit lesion Plaque rupture in different artery than culprit lesion Adapted with permission from Falk E, et al. Circulation. 1998;92: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Adapted from Rioufol G, et al. Circulation. 22;16: Slide courtesy of David Kandzari. 2

3 Frequency of Multiple Active Plaques in Patients With ACS 8% of Patients With 2 Plaques Atherothrombosis* is the Leading Cause of Death Worldwide 1 Pulmonary Disease N=24 Injuries 9 25 AIDS 9.7 Patients (%) Cancer Infectious Disease Atherothrombosis* Frequency of multiple active plaque ruptures beyond the culprit lesion Causes of Mortality (%) ACS indicates acute coronary syndrome. Adapted from Rioufol G, et al. Circulation. 22;16: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: *Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report 21. Geneva: WHO; 21. Reprod.with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Thrombus Formation and ACS Old Terminology: New Terminology: Plaque Disruption/Fissure/Erosion Thrombus Formation UA NQMI STE-MI Non-ST-Segment Elevation Acute Coronary Syndrome (ACS) ST-Segment Elevation Acute Coronary Syndrome (ACS) Epidemiology of ACS in the United States Single largest cause of death 515,24 US deaths in 2 1 in every 5 US deaths Incidence 1,1, Americans will have a new or recurrent coronary attack each year and about 45% will die* 55, new cases of angina per year Prevalence 12,9, with a history of MI, angina, or both * Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. ACS indicates acute coronary syndrome; MI, myocardial infarction; ARIC, Atherosclerotic Risk in Communities; and CHD, coronary heart disease. From American Heart Association. Heart Disease and Stroke Statistics 23 Update. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: 3

4 Risk and Risk Stratification Braunwald Classification of Risk for Patients with Unstable Angina Feature History Character of Pain Clinical Findings ECG Cardiac Markers High Risk At least 1 of the following features must be present: Accelerating tempo of ischemic symptoms in preceding 48 hrs Prolonged ongoing (>2 min) rest pain Pulmonary edema New or worsening MR murmur S 3 or new/worsening rale Hypotension, bradycardia, tachycardia Age >75 years Angina at rest with transient ST-segment changes >.5 mv New or presumed new BBB Sustained ventricular tachycardia Elevated (TnT or TnI >.1 mg/ml) Intermediate Risk No high-risk feature but must have 1 of the following: Prior MI, peripheral or cerebrovascular disease, CABG, or prior aspirin use Prolonged (>2 min) rest angina, now resolved, with moderate or high likelihood of CAD Age > 7 years T-wave inversions >.2 mv Pathological Q waves Slightly elevated (TnT >.1 but <.1 ng/ml) Low Risk No high- or intermediate-risk feature but may have any of the following features: New-onset or progressive CCS Class III or IV angina the past 2 weeks Normal or unchanged ECG during an episode of chest discomfort Normal Available at: GUSTO IIb: Correlation of 6-Month Mortality With Baseline ECG Findings in Patients With ACS Cumulative Mortality (%) Days From Randomization ST ACS STEMI with fibrinolytics T-wave inversion TIMI Risk Score Age >65 years >3 CAD Risk Factors Prior Coronary Stenosis >5 % ST deviation >2 Anginal events <24 hours ASA in last 7 days Elevated Cardiac Markers (CK-MB or troponin) GUSTO indicates Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes; ECG, electrocardiogram; ACS, acute coronary syndrome; and STEMI, ST-segment elevation myocardial infarction. Figure adapted with permission from Savonitto S, Ardissino D, Granger CB, et al. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA. 1999;281: Copyright 1999, American Medical Association. All rights reserved. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Reproduced with permission from Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-st elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2;284: Copyright 2, American Medical Association. All rights reserved. 4

5 The TIMI Risk Score and Incidence of Adverse Ischemic Events in Patients with NSTE-ACS Death, MI, or Urgent Revascularization (%) Reproduced with permission from Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-st elevation MI: a method for prognostication and therapeutic decision making. JAMA.. 2;284: Copyright 2, American Medical Association. All rights reserved / /7 Number of Risk Factors Prognostic Value of Troponin T or I in ACS: A Meta-Analysis % RR 3.9 ( ) 1.9 Death 6.4 Neg Pos (Trop I + T) 6.7 RR 3.8 ( ) 2.8 Death/MI Figure reproduced with permission from Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of troponin in patients with non-st elevation acute coronary syndrome: a meta-analysis. J Am Coll Cardiol. 21;38: Slide modified with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Troponin I Levels and Mortality in Patients with NSTE-ACS % Mortality at 42 Days <.4.4- < < <5. Troponin I Level 5.- <9. >9. Adapted with permission from Antman EA, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335: Copyright 1996, Massachusetts Medical Society. All rights reserved. Initial Therapies and Management 5

6 ACC/AHA Class I Recommendations for Initial Management and Anti-Ischemic Therapy Pathogenesis of Acute Coronary Syndromes: The integral role of platelets Bed rest Continuous ECG Monitoring Supplemental O 2 to maintain SaO 2 >9% NTG (IV or PO as dictated clinically) Beta-blockers (PO and/or IV) IV Morphine prn pain, anxiety, and/or CHF IABP for hemodynamic instability ACEI for persistent hypertension in patients with LV systolic dysfunction or CHF Plaque Fissure or Rupture Platelet Adhesion Platelet Activation Platelet Aggregation Thrombotic Occlusion Available at: Platelets and Anti- Platelet Therapies The Role of Platelets in Atherothrombosis 1 Adhesion 3 Aggregation 2 Activation Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: 6

7 ADP Ticlopidine Clopidogrel The Platelet IIb/IIIa receptors Epinephrine GP IIb/IIIa inhibitors Collagen Arachidonic Acid Aspirin Thrombin Heparin LMW Heparin Direct Thrombin Inhibitors fibrin Treatment of Unstable Angina Results of a study from the Montreal Heart Institute % Developing MI placebo aspirin heparin ASA+hep Treatment Data from Theroux P, Quimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319: Platelet Inhibition With GP IIb/IIIa Inhibitors The Primary Composite End Point in the CURE Trial % With Event Placebo + Aspirin Clopidogrel + Aspirin 2% RRR P = Follow-up (months) Reproduced with permission from Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Engl J Med. 2;342: Copyright 2, Massachusetts Medical Society. All rights reserved. Reproduced with permission from Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 21;345: Copyright 21, Massachusetts Medical Society. All rights reserved. 7

8 CURE: Primary End Point in Subgroups Subgroup Placebo Plavix RR ST Changes 14.3% 11.5%.79 PURSUIT Primary End Point No ST Changes 8.7% 7.%.8 Enzyme Elevation 13.1% 1.7%.81 No Enzyme Elevation 1.9% 8.8%.79 Post-Randomization Revascularization No Post-Random Revascularization 13.9% 1.1% 11.4% 8.1% Data from Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med. 21;345: Reproduced with permission from the PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998;339: Copyright 1998, Massachusetts Medical Society. All rights reserved. CV Death/MI CVA/Ref Ischemia CV Death MI CURE Secondary End Points Endpoint CV Death/ MI/CVA Stroke Refract Ischemia Major Bleeding Placebo 11.7% 19.2% 5.4% 6.68% 1.4% 9.4% 2.7% Plavix 9.28% 16.68% 5.6% 5.19% 1.2% 8.8% 3.6% RR P Value.5.4 NA <.1 NA NA.3 Data from Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med. 21;345: PURSUIT Primary Composite End Point Placebo Integrilin P=.4 16 P= % % P= % % 9.1% 7.6% Hrs 7 Days 3 Days Not powered for statistical analysis Reproduced with permission from the PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998;339: Copyright 1998, Massachusetts Medical Society. All rights reserved. % With Death or MI 8

9 Meta-Analysis of IV GP IIb/IIIa Inhibitors in NSTE-ACS: Death or MI at 3 Days Study Placebo IV Gp IIb/IIIa Odds Ratio 95% CI PRISM 7.1% 5.8%* PRISM-PLUS 12.% 8.7% %* PARAGON-A 11.7% 1.3% % PURSUIT 15.7% 13.4% % PARAGON-B 11.4% 1.6% GUSTO-IV 8.% (24h) 8.2% (48h) 9.1% Overall 11.8% 1.8% t Gp IIb/IIIa Better Placebo Better P=.15 * Without heparin. With/without heparin. (l), Low dose; (h), High-dose. Adapted with permission from Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndrome: a meta-analysis of all major randomised clinical trials. Lancet. 22;359: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: GP IIb/IIIa Therapy and Mortality (3 day) in Diabetics with NSTE-ACS PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled Mortality: 6.2% vs. 4.6% OR=.74 CI= P=.7 Adapted with permission from Roffi M, et al. Circulation. 21;14: Relative Risk of Death (versus placebo Rx) GP IIb/IIIa Inhibitor NSTE-ACS Studies Analysis Risk-Adjusted Mortality at 3 Days Odds Ratio for Mortality at 3 Days Antithrombotic and Antiplatelet Therapy in ACS NRMI 1 Odds Ratio.88 95% CI Boersma GP IIb/IIIa Inhibitor Favored (aspirin + heparin) Control Arm Favored (aspirin + heparin) Data from (1) Peterson ED, Pollack CV Jr, Roe MT, et al. Early use of glycoprotein IIb/IIIa inhibitors in non-st-elevation acute myocardial infarction: observations from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol. 23;42:45-53 and (2) Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndrome: a meta-analysis of all major randomised clinical trials. Lancet. 22;359: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: ACC/AHA Guideline Update for UA and NSTEMI

10 Milestones in ACS Management Anti-Thrombin Rx Heparin Anti-Platelet Rx Aspirin Treatment Strategy Conservative Ischemic risk Bleeding risk GP IIb/IIIa blockers PRISM-PLUS ESSENCE PURSUIT LMWH Clopidogrel TACTICS TIMI-18 Early invasive REPLACE 2 CURE Bivalirudin SYNERGY OASIS-5 ACUITY PCI ~ 5% stents ~85% stents Drug-eluting stents ICTUS Adapted from and with the courtesy of Steven Manoukian, MD. [ Fondaparinux ] ISAR-REACT 2 ACC/AHA Recommendations for Antiplatelet Therapy in Patients with NSTE-ACS Class IIa GP IIb/IIIa inhibitor in patients with high-risk features if invasive strategy not planned GP IIb/IIIa inhibitor in patients receiving clopidogrel if cardiac cath and PCI planned Class IIb GP IIb/IIIa inhibitor in patients without high-risk features and PCI not planned Class III Abciximab in patients in whom PCI is not planned Available at: ACC/AHA Recommendations for Antiplatelet Therapy in Patients with NSTE-ACS Class I ASA Clopidogrel if ASA-allergic or intolerant Clopidogrel in addition to ASA if early invasive approach not planned Clopidogrel should be withheld for 5-7 days if CABG planned GP IIb/IIIa inhibitor if cardiac cath and PCI planned Contraindications to GP IIb/IIIa Rx Active or recent bleeding (4-6 weeks) Severe hypertension (SBP >18-2 mm Hg; DBP >11 mm Hg) Any hemorrhagic CVA (+/- intracranial neoplasm, AVM, or aneurysm) Any CVA within 3 days 2 years Major surgery or trauma within 4-6 weeks Thrombocytopenia ( <1,/mm 3 ) Bleeding diathesis/warfarin with elevated INR (Doses must be avoided with renal insufficiency or failure) Available at: 1

11 Antithrombin Therapy Studies and Recommendations Death, MI or Recurrent Angina ESSENCE Results 3% 25% 2% 15% 1% 5% Unfractionated Heparin Enoxaparin (Lovenox) P =.2 Risk Reduction 16.2% Days After Randomization Adapted with permission from Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997;337: Copyright 1997, Massachusetts Medical Society. All rights reserved Comparison of Heparin + ASA vs ASA Alone Summary Relative Risk.67 ( ).1 Heparin + ASA 55/698=7.9% 1 1 RR: Death/MI ASA Alone 68/655=1.4% Theroux RISC Cohen 199 ATACS Holdright Gurfinkel ASA indicates acetylsalicylic acid; RISC, Research on InStability in Coronary artery disease; ATACS, Antithrombotic Therapy in Acute Company Syndromes; RR, relative risk; and MI, myocardial infarction. Data from Oler A, Whooley MA, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Death, MI or Urgent Revascularization TIMI 11B: Enoxaparin vs. Heparin in NSTE-ACS Unfractionated Heparin Enoxaparin (Lovenox) Days Adapted from Antman EM, et al. Circulation. 1999;1: % 14.2 % p =.3 Relative Risk Reduction = 15% 11

12 Guidelines for the Use of Enoxaparin in Patients with NSTE-ACS 1 mg/kg SQ q12 hours (actual body weight) An initial 3 mg IV dose can be considered Adjust dosing if CrCl <3 cc/min 1 mg/kg SQ q24 hours Do not follow PTT; do not adjust based on PTT Stop if platelets by 5% or below 1,/mm 3 If patient to undergo PCI: -8 hours since last SQ dose: no additional antithrombin therapy 8-12 hours since last SQ dose:.3 mg/kg IV immediately prior to PCI Early Invasive Strategy Studies and Recommendations in Patients with NSTE-ACS ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS Class I Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy Dose of UFH 6-7 U/kg (max 5) IV followed by infusion of U/kg/hr (initial max 1 U/hr) titrated to aptt times control Dose of enoxaparin 1 mg/kg subcutaneously q12 hr; the first dose may be preceded by a 3-mg IV bolus Class IIa Enoxaparin is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours Available at: TACTICS 2% 16% 12% 8% Initial Medical Rx Early Cath + PTCA 19.4% 15.9% 4% Months Adapted with permission from Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 21;344: Copyright 21, Massachusetts Medical Society. All rights reserved. 12

13 TACTICS Trial Results Based on Troponin Initial Medical Rx 25% 2% 15% 1% 5% Early Cath + PTCA P=NS Negative Troponin P<.1 Positive Troponin Adapted with permission from Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 21;344: Copyright 21, Massachusetts Medical Society. All rights reserved. The Primary Composite Ischemic End Point in RITA-3 Reproduced with permission from Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-st-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomised Intervention Trial of Unstable Angina. Lancet. 22;36: Benefit of Invasive Strategy by Troponin and ST Changes 3 25 Death, MI, or Rehospitalization for ACS at 6 Months Conservative Invasive P=NS 25.* P< P=NS 24.5* P<.1 Meta-Analysis of Trials of Early Cardiac Cath and Revascularization Versus Initial Medical Therapy Alone in Patients with NSTE-ACS CV Events (%) * * 5 5 TnT TnT + No ST change ST change TnT indicates troponin T; and ST, ST segment. Data from (1) Morrow DA, et al. JAMA. 21;286: and (2) Cannon CP, et al. N Engl J Med. 21;344: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Reproduced with permission from Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-st-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomised Intervention Trial of unstable Angina. Lancet. 22;36:

14 Invasive vs Conservative Strategy for UA/NSTEMI VANQWISH Conservative MATE TIMI IIIB ISAR- COOL RITA-3 VINO TRUCS TACTICS- TIMI 18 FRISC II Invasive UA indicates unstable angina, NSTEMI, non ST-segment myocardial infarction; ISAR, Intracoronary Stenting and Antithrombic Regimen Trial; RITA, Randomized Intervention Treatment of Angina; VANQWISH, Veterans Affairs Non-Q- Wave Infarction Strategies in Hospital study; MATE, Medicine vs Angioplasty for Thrombolytic Exclusions trial; TACTICS-TIMI18, Treat Angina with Aggrastat and Determine Cost of Therapy with Invasive or Conservative Strategy; and FRISC, Fragmin during InStability in Coronary artery disease. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: Conclusions Recent ACS Trials OASIS 5 Fondaparinux has less bleeding than enoxaparin, non-inferior clinical outcomes at 9 days, and less death and death/mi at 6 months; UFH is probably required in the cath lab dose unknown. ACUITY Bivalirudin with provisional GPI has less bleeding than UFH/LMWH + GPI, comparable ischemic outcomes, and superior net clinical benefit. Bivalirudin + GPI is comparable to UFH/LMWH + GPI Conclusions-Recent ACS Trials ICTUS In troponin (+) patients, a selective invasive management strategy may be an option, but there was a high use of angiography and revascularization in the selective arm. ISAR REACT 2 Clopidogrel loading alone is not sufficient in ACS patients; Troponin (+) patients derive significant benefit with GP IIb/IIIa antagonists SYNERGY Enoxaparin is an alternative in invasively managed patients, but may have slightly higher bleeding, especially when UFH is indiscriminately added in the cath lab Conclusions ACS Management NSTE-ACS is common and associated with high morbidity and mortality Early invasive strategy is preferred in higher-risk individuals Early initiation of appropriate antiplatelet and antithrombin therapy is important for reduction of ischemic events Balancing the risk of ischemic and bleeding complications is essential to maximize clinical benefit in individual patients The evidence base and strategies for optimal management of NSTE-ACS continue to evolve 14

15 ACC/AHA Class I Recommendations for Invasive and Medical Strategies in Patients with NSTE-ACS Class I An early invasive strategy in patients with any high-risk indicators: Recurrent angina/ischemia at rest or with low-level activities Elevated troponin New or presumed new ST-segment depression Recurrent angina/ischemia with CHF Sx and S 3 gallop, pulmonary edema, worsening rales, or new or worsening MR High-risk findings on noninvasive stress testing Depressed LVEF (<4%) Hemodynamic instability Sustained ventricular tachycardia PCI with 6 months or prior CABG In the absence of any of the above high-risk indicators, either an early conservative or an early invasive strategy STEMI Available at ST Elevation Acute Myocardial Infarction (STEMI) STEMI Quinn Capers, IV, MD, FACC, FSCAI Assistant Professor Director, Peripheral Vascular Interventions, OSU Ross Heart Hospital Director, Cath Lab, University Hospital East 15

16 EKG: Acute anterior STEMI Artery Opened Emergently Cardiac Cath Lab Before stent, artery closed, no blood flow to heart After stent, artery open, blood flow to heart restored 16

17 Combination of blood clot and plaque removed from artery STEMI: Vascular Biology Normal coronary artery Lined with endothelial cells No resident inflammatory cells (monocytes/macrophages/lym phocytes Vasodilatory>Vasoconstriction Antithrombotic Atherosclerotic plaque Lined with endothelial cells Monocytes/macrophages infiltrate vascular wall and destabilize plaque Vasoconstriction>Vasodilatory Prothrombotic S-T segment Elevation acute Myocardial Infarction (STEMI) Definition: acute myocardial infarction that occurs when coronary artery is completely occluded Differs from non-st elevation MI in, which coronary artery is often not completely occluded Coronary artery is clogged with combination of plaque and thrombus STEMI: Vascular Biology Features of the stable plaque: Thick fibrous cap separating sub-intima from flowing blood High ratio of connective tissue: lipids Low density of inflammatory cells Low enzymatic activity within plaque: cold Less prone to rupture 17

18 STEMI: Vascular Biology Features of the unstable or vulnerable plaque: Thin fibrous cap separating sub-intima from flowing blood High ratio of lipids to connective tissue High density of inflammatory cells, especially at shoulders High enzymatic activity within plaque: warm More prone to rupture STEMI: Vascular Biology Changing the vulnerable plaque to a quiescent, stable plaque is major focus of treatment of CAD patients Statins (lipid lowering drugs) BP control Inhibition of renin angiotensin system Tobacco avoidance STEMI: Vascular Biology STEMI: Pathophysiology Unstable or vulnerable plaque: Unstable angina, acute MI (Non-STEMI or STEMI) High systemic inflammatory state (CRP, ESR, IL1) Acute coronary syndromes A T 18

19 STEMI: Pathophysiology Plaque rupture (7%) or endothelial erosion (3%) Results in flowing blood coming in contact with plaque contents Plaque contents are highly thrombogenic Plaque + overlying thrombus impairs blood flow to myocardium STEMI: Clinical Presentation ST segment elevation MI (STEMI) Severe angina, shortness of breath, or both Physical exam can separate high from low risk pt Rales on lung auscultation, gallops on cardiac auscultation, tachycardia, low BP EKG: ST segment elevation in at least two contiguous leads Coronary Thrombosis: Clot begets Clot Ruptured plaque promotes thrombin formation and recruits platelets to site Activated platelets accelerate thrombin formation Thrombin stimulates platelet activation STEMI: Clinical Presentation To Diagnose Acute MI, 2 of these 3 must be present: Discomfort suspicious for cardiac ischemia (usually deep seated chest, arm, neck, or back discomfort) EKG abnormalities consistent with ischemia or infarction (ST segment depression or elevation or T wave inversion) Elevated markers of myocardial necrosis in the bloodstream (CPK, CPK-MB, troponin I, troponin T, myoglobin) 19

20 Acute Coronary Syndromes: Treatment Principles Restore normal coronary blood flow as soon as possible ( Time is muscle ) Address coronary thrombosis, interrupt cycle Increase diameter of coronary artery to allow perfusion Main principle: do not delay immediate reperfusion STEMI: Specifics of Treatment Antiplatelet therapy ASA, Clopidogrel Antithrombin therapy Heparin, LMWH, other antithrombins Beta blocker Acute Coronary Syndromes: Treatment Principles Decrease myocardial oxygen demand Decrease HR, BP Interrupt sympathetic nervous system/catecholamine stimulation of heart STEMI: Specifics of Treatment Nitroglycerin Supplemental Oxygen Anxiolytic 2

21 STEMI: Specifics of Treatment STEMI: Reperfusion Therapy Reperfuse without delay! Reperfuse without delay! Reperfuse without delay! Thrombolytic therapy Emergent cardiac cath/angioplasty/stent Emergent CABG STEMI: Specifics of Treatment Benefits of immediate reperfusion: Improves chances of survival Minimizes myocardial damage STEMI: Reperfusion Therapy Thrombolytic therapy Medications that enhance endogenous clot dissolving substances Examples: tpa, rpa, streptokinase Given IV, dissolve coronary thrombus Leaves behind ruptured plaque Success rate: 65-75% 21

22 STEMI: Reperfusion Therapy Emergent cardiac cath/angioplasty/stent Fastest way to open coronary artery Most complete method of reperfusion Allows risk stratification by visualizing other coronary arteries and assessing LV function and pressure Success rate: 95%+ Thrombolytic Therapy vs Emergent Stent Placement In multiple head-to-head studies, percutaneous intervention in STEMI pts proved superior to fibrinolytic drug therapy (better survival, better myocardial salvage, lower complication rates) Often used together (STEMI pt in small hospital placed on fibrinolytic drug, transported emergently to larger center for emergent cath) The point is : whether using fibrinolytic therapy or emergent coronary intervention, get the artery open as soon as possible!!! It can mean the difference between a relatively normal life, life with severe heart disease, and death. Thrombolytic Therapy vs Emergent Stent Placement Fibrinolytic drug tx Improves survival in STEMI pts Works within 9 min of initiation of tx Initial success in 65-75% of pts 2-3% reocclude artery Intracranial bleed in approx 1% Artery left with severe stenosis Available in most, if not all hospitals Percutaneous intervention Improves survival in STEMI pts Works within 3 min of initiating cath Initial success in >95% of pts <1% reocclude artery Intracranial bleed risk <.1% Artery left with % residual stenosis Available in <1/3 of hospitals Acute Coronary Syndromes: Treatment:STEMI Delays are a major problem, with delays at several steps: Patient delays seeking medical help (denial, poor access, social issues) Delay in ER staff performing EKG Delay in EKG being presented to MD for interpretation Delay in drugs being mixed in pharmacy and administered to pt Delay in transporting pt from ER to cath lab or from one hospital to another Delay in cath lab staff coming in from home 22

23 STEMI: The Aftermath Therapies to start before hospital discharge: ACE inhibitors (prevent post-mi cardiac enlargement or remodeling, and sudden death) Statins (decrease lipids and change vulnerable, rupture-prone plaques to stable plaques) Aldosterone receptor antagonists (improve survival in pts with severe LV dysfunction post-mi) (These are all in addition to ASA, clopidogrel, beta-blocker) STEMI: Summary Coronary thrombosis is a hallmark of acute coronary syndromes Much of the therapy for STEMI is directed at interrupting the vicious cycle of thrombosis (e.g., ASA, clopidogrel, heparin, IIb/IIIa blockers) In STEMI, emergent reperfusion can be lifesaving, the sooner the better We must continue efforts to decrease delays in opening the occluded artery in STEMI pts STEMI: Summary Unstable or vulnerable plaques are lipidfilled, tense, metabolically active, and prone to rupture, causing acute coronary syndromes A main focus of treating CAD pts is transforming vulnerable plaques to stable plaques. Statins are the drugs with the most evidence supporting this. 23