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Dr. R.V.S.N.Sarma, M.D., M.Sc (Canada)

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1 Dr. R.V.S.N.Sarma, M.D., M.Sc (Canada)
Consultant Physician and Chest Specialist 1, Jayanagar, Tiruvallur, Chennai (04116) – , Mobile

2 Ischemic Heart Disease
Diagnosis & Management

3 We’ve come a long way in the treatment of MI

4 “ There’s too much confusion,
Never, I can’t get neither no relief ” Jimi Hendrix, Purple Haze, 1968

5 “In this world, nothing can be said to be certain except death and taxes.”
Benjamin Franklin 13 November 1789 (letter)

6 Lysis or Life-flight ?

7 Comorbidity of Atherosclerotic Disease a major health burden
Atherothrombosis major complications of atherosclerosis are thrombosis, with local occlusion or distal embolization CAD CVA PAD Aronow WS, Ahn C. Am J Cardiol. 1994;74:64–65.

8 Endothelial Dysfunction
Atherosclerosis Time-line Complicated Lesion/ Rupture Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Atherosclerosis is a progressive disease involving the development of arterial wall lesions. As they grow, these lesions may narrow or occlude the arterial lumen. Complex lesions may also become unstable and rupture, leading to acute coronary events, such as unstable angina, myocardial infarction, and stroke. Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998; 82(suppl 10A): Endothelial Dysfunction From First Decade From Third Decade From Fourth Decade Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104). 9

9 Left Coronary Artery

10 Right Coronary Artery

11 Overview of CAD Presentation
Assessment of CAD likelihood Risk stratification based on findings Anti-ischemic drug therapy Anti-platelet/ anti thrombotic therapy Invasive versus conservative strategy Primary PTCA versus Thrombolytic Rx. Secondary prevention and risk factor modification

12 Clinical Assessment The two critical questions
What is the likelihood that the signs and symptoms represent ACS secondary to obstructive CAD ? What is the likelihood of an adverse clinical outcome? like risk of death and nonfatal cardiac ischemic events (new or recurrent MI, recurrent UA, disabling angina that requires hospitalization, and/or urgent coronary revascularization)

13 History - Likelihood of ischemia
The 5 most important factors, ranked in the order of importance, are Nature of the anginal symptoms Prior history of CAD Sex Age Number of traditional risk factors present The 5 most important factors derived from the initial history that relate to the likelihood of ischemia due to CAD, ranked in the order of importance, are 1) the nature of the anginal symptoms, 2) prior history of CAD, 3) sex, 4) age, and 5) the number of traditional risk factors present The presence or absence of traditional risk factors ordinarily should not be used to determine whether an individual patient should be admitted or treated for ACS. They are only weakly predictive of the likelihood of acute ischemia and are far less important than are symptoms, ECG findings, and cardiac markers However, the presence of these risk factors does appear to relate to poor outcomes in patients with established ACS Diabetes and HTN have significantly higher mortality rate and risk of acute heart failure “Smokers' Paradox"

14 Classical Angina Angina is characterized as a deep, poorly localized
chest or arm discomfort that is reproducibly associated with physical exertion or emotional stress and is relieved promptly (in less than 5 min) with rest and/or the use of sublingual nitroglycerin (NTG)

15 Clinical Classification of Chest Pain
Typical angina (definite) 1) substernal chest discomfort with a characteristic quality and duration that is ) provoked by exertion or emotional stress and 3) relieved by rest or nitroglycerin Atypical angina (probable) meets 2 of the of characteristics Noncardiac chest pain meets  1 of the typical angina characteristics J Am Coll Cardiol. 1983;1:574, Letter

16 Differential Diagnosis of Prolonged Chest Pain
AMI Aortic dissection Pericarditis Atypical angina pain associate with hypertrophic cardiomyopathy Esophageal, other upper gastrointestinal, or biliary tract disease Pulmonary disease pneumothorax embolus with or without infarction pleurisy: infectious, malignant, or immune disease-related Hyperventilation syndrome Chest wall skeletal neuropathic Psychogenic

17 Chest Pain Checklist Dr.Sarma@works YES
Ongoing chest discomfort ( 20 min and < 12 hours) Oriented, can cooperate Age > 35 y (> 40 if female) ECG done High-risk profile * Heart rate  100 bpm Blood pressure  100 mm Hg Pulmonary edema (rales > 1/2 way up) Shock NO History of stroke or TIA Known bleeding disorder Active internal bleeding in past two weeks Surgery or trauma in past two weeks Terminal illness Jaundice, hepatitis, kidney failure Use of anticoagulants Systolic/diastolic blood pressure Right arm ____/____ Left arm ____/____ 1. Pain began ____ AM/PM 2. Arrival time ____ AM/PM 3. Begin transport ____ AM/PM 4. Hospital arrival ____ AM/PM Check each finding. If all [YES] boxes are checked and ECG indicates ST elevation or new BBB, reperfusion therapy with fibrinolysis or primary PTCA may be indicated. Fibrinolysis is generally not indicated unless all [NO] boxes are checked and BP  180/110 mm Hg. * Transport to a facility capable of angiography and revascularization if needed Adapted from the Seattle/King County EMS Medical Record

18 Acute Coronary Syndrome
Ischemic Discomfort Unstable Symptoms History Physical Exam No ST-segment elevation ST-segment elevation ECG (10 min) Acute coronary syndrome has evolved as a useful operational term to refer to any constellation of clinical symptoms that are compatible with acute myocardial ischemia. It encompasses AMI (ST-segment elevation and depression, Q wave and non-Q wave) as well as UA. These guidelines focus on 2 components of this syndrome: UA and NSTEMI. Up to 25% of patients with NSTEMI and elevated CK-MB go on to develop Q-wave MI, whereas the remaining 75% have non-Q-wave MI. Nonspecific ST-segment and T-wave changes, usually defined as ST-segment deviation of less than 0.05 mV or T-wave inversion of less than or equal to 0.2 mV, are less helpful than the foregoing findings. The common alternative causes of ST-segment and T-wave changes must be considered. In patients with ST-segment elevation, the diagnoses of LV aneurysm, pericarditis, Prinzmetal's angina, early repolarization, and Wolff-Parkinson-White syndrome should be considered. Central nervous system events and drug therapy with tricyclic antidepressants or phenothiazines can cause deep T-wave inversion. Cardiac Biomarkers Unstable NSTEMI STEMI Angina (Non-Q MI) (Q-wave MI) (positive cardiac biomarker)

19 ACC/AHA Classifications Expert Opinion and Recommendations
IIa IIb III Intervention is useful and effective Evidence conflicts/opinions differ but leans towards efficacy Evidence conflicts/opinions differ but leans against efficacy Intervention is not useful/effective and may be harmful The weight of effidence is applied to a particular area and a Class of Recommendations is formulated. The classes range from I – III, and Class II is subdivided into a and b. Class I Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment Class IIa weight of evidence/opinion is in favor of usefulness/efficacy Class IIb usefulness/efficacy is less well established by evidence/opinion Class III Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful Most physicians would suggest that: Class I and IIa should be practiced Class IIb should be given careful consideration for an individual patient. Class III should not be practiced JACC 1999; Vol 33, No 7:

20 12 Lead Resting ECG should be recorded in all patients with symptoms suggestive of angina pectoris normal in  50% of patients a normal ECG does not exclude severe CAD; however, it does imply normal LV function with favorable prognosis

21 Tools for Risk Stratification
The 12-lead ECG lies at the center of the decision pathway for the evaluation and management of patients with ischemic discomfort. A recording made during an episode of presenting symptoms is particularly valuable. Importantly, transient ST-segment changes (> 0.05 mV) that develop during a symptomatic episode at rest and that resolve when the patient becomes asymptomatic strongly suggest acute ischemia and a very high likelihood of underlying severe CAD

22 Risk Stratification: abnormal rest ECG
Evidence of >1 prior MI (Q waves or R wave in lead V1 for posterior infarction) A "QRS score" to indicate the extent of old or new MI persistent ST-T wave inversions, particularly in leads V1 to V3 of the rest ECG, is associated with an increased likelihood of future acute coronary events and a poor prognosis LV hypertrophy by ECG criteria in a patient with angina pectoris is also associated with increased morbidity and mortality A decreased prognosis is also likely when the ECG shows left bundle-branch block, bifascicular block (often left anterior fascicular block plus right bundle-branch block), second- or third- degree atrioventricular block, atrial fibrillation or ventricular tachyarrhythmias Am J Cardiol 1982;49:

23 Risk stratification: Chest X-Ray
often normal in patient with stable angina pectoris usefulness as a routine test is not well established findings associated with poorer long-term prognosis cardiomegaly LV aneurysm pulmonary venous congestion left atrial enlargement calcium in the coronary arteries

24 Cardiac Troponins Advantages Disadvantages Clinical recommendations
powerful tool for risk stratification greater sensitivity and specificity than CK-MB detection of recent MI up to 2 weeks after onset Disadvantages low sensitivity in very early phase of MI (< 6 h after symptom onset) limited ability to detect late minor reinfarction Clinical recommendations useful as a single test to efficiently diagnose NSTEMI (including minor myocardial damage), with serial measurements

25 CK-MB Advantages Disadvantages Clinical recommendations
rapid, cost-efficient, accurate assays ability to detect early reinfarction Disadvantages loss of specificity in setting of skeletal muscle disease or injury, including surgery low sensitivity during very early MI (< 6 h after symptom onset) or later after symptom onset (> 36 h) and for minor myocardial damage (detectable by troponins) Clinical recommendations prior standard and still acceptable diagnostic test in most clinical circumstances

26 Myoglobin Advantages Disadvantages Clinical recommendations
high sensitivity useful in early detection of MI detection of reperfusion most useful in ruling out MI Disadvantages very low specificity in setting of skeletal muscle injury or disease rapid return to normal range limits sensitivity for later presentations Clinical recommendations should not be used as only diagnostic marker because of lack of cardiac specificity

27 Tools for Risk Stratification
Biomarkers are of critical importance in the evaluation of patients with UA/NSTEMI. The troponins offer great diagnostic sensitivity because of your ability to identify patients with lesser amounts of myocardial damage. Nevertheless, these lesser amounts of damage are associated with high-risk patients with ACSs because they are thought to represent microinfarctions that result from microemboli from an unstable plaque.

28 Serum Cardiac Markers CK-MB subfomes for Dx within 6 hrs of MI onset
cTnI and cTnT efficient for late Dx of MI CK-MB subform plus cardiac-specific troponin best combination Do not rely solely on troponins because they remain elevated for 7-14 days and compromise ability to diagnose recurrent infarction

29 Myocardial Markers

30

31 Enzymatic Criteria for Diagnosis of Myocardial Infarction
Serial increase, then decrease of plasma CK-MB, with a change > 25% between any two values CK-MB > U/L or > 5% total CK activity increasing MB-CK activity > 50% between any two samples, separated by at least 4 hrs if only a single sample available, CK-MB elevation > twofold beyond 72 hrs, an elevation of troponin T or I or LDH-1 > LDH-2

32 The Progressive Development of Cardiovascular Disease
Risk Factors Endothelial Dysfunction Atherosclerosis CAD Myocardial Ischemia Coronary Thrombosis Myocardial Infarction Atherosclerotic disease is a progressive disease as shown in this slide. Many therapeutic interventions are aimed at specific cardiovascular conditions. These interventions may be directed at alleviating symptoms or preventing progression to more serious stages or both. Angiotensin-converting enzyme (ACE) inhibitors have been studied, for example, in patients with hypertension, who are at the top of this progression pathway. These studies looked only at the effects on blood pressure, however, and did not address the long-term question of risk reduction. Other clinical trials with ACE inhibitors have been designed to investigate the effects of these agents on the morbidity and mortality following an acute myocardial infarction. Arrhythmia & Loss of Muscle Remodeling Ventricular Dilation Congestive Heart Failure Endstage Heart Disease 10

33 Slide 3L The pathologic process of atherothrombosis begins with the development of atherosclerotic plaque within the arterial lumen. A number of factors may lead to fissuring, cracking, or rupture of the plaque, exposing thrombogenic components such as collagen and von Willebrand factor, which cause platelets to adhere to the damaged area, forming a thrombus. Thrombi may then become incorporated into atheroma, thereby increasing the size of the plaque and further constricting the arterial lumen. These events may be clinically silent. If the plaque is then stabilized, the process may remain asymptomatic. However, if the thrombus is unstable and becomes dislodged, the resulting embolus may be carried throughout the circulation or become lodged, most often in a vascular bifurcation, thereby obstructing circulation. Alternatively, a burgeoning thrombus may itself occlude the artery. In either of these cases, an acute vascular event—myocardial infarction, unstable angina, ischemic stroke, transient ischemic event, or even cardiovascular death—may ensue. 4

34 Cardiac Enzyme bio-markers

35 MYOFIBER STRUCTURE TnI TnC TnT Tropomyosin Actin

36 Inferior MI changes fully evolved

37 Posterior MI

38 ST ↓ - Ischemia Lateral wall

39 ST segment ↑– Acute evolving MI

40 ST segment ↑– Inferio-lateral MI

41 Evolution of Acute MI

42 Acute MI Anterior wall

43 Anterio-septal MI with RBBB

44 Extensive Anterio-lateral MI

45 Fully Evolved MI Anterioseptal

46 MI inferio-posterior

47 Inferio-posterior MI with RV MI

48 Risk Factors for Atherosclerotic Disease
Non-modifiable Age Family history Sex Modifiable Cigarette smoking Diabetes mellitus Hyperlipidemia Hypertension Obesity Physical inactivity Hoeg JM. JAMA. 1997;277:1387–1390.

49 Vascular Endothelium Endothelium as an organ
1 to 6 x 1013 cells monolayer weighs 1 kg covers 6 tennis courts Modulator of vascular tone nitric oxide (NO) prostaglandin I2 (PGI2, prostacycline) Regulator of hemostasis antithrombotic prothrombotic Anticoagulant: GAGs/AT III TFPI Thrombomodulin Profibrinolytic: t-PA u-PA Binding sites for plasminogen PA receptors Platelet inhibitory: PGI2 (prostacycline) Nitric oxide ADPase Carbon monoxide Procoagulant: Tissue factor Binding sites for coagulation factors and fibrin Antifibrinolytic: PAI TAFI Platelet activating: vWF PAF Fibronectin Endothelin-1 TXA2 Antithrombotic Vasodilation Prothrombotic Vasoconstriction

50 ACUTE CORONARY SYNDROME
No ST Elevation ST Elevation NSTEMI Unstable Angina NQMI QwMI Myocardial Infarction

51 ACUTE CORONARY SYNDROMES (ACS)

52 CAUSES OF UA/NSTEMI Mechanical Obstruction Thrombosis . Dynamic  MVO2
Inflammation/ Infection Mechanical Obstruction Thrombosis . Dynamic Obstruction  MVO2 Braunwald, Circulation 98:2219, 1998 Inflammation/ Infection

53 ED MANAGEMENT OF UA/NSTEMI
No recurrent pain; Neg follow-up studies Nondiagnostic ECG Normal serum cardiac markers Observe Follow-up at 4-8 hours: ECG, cardiac markers Neg: nonischemic discomfort;low-risk UA/NSTEMI YES NO ST and/or T wave changes Ongoing pain + cardiac markers Hemodynamic abnormalities Recurrent ischemic pain or + UA/NSTEMI follow-up studies Diagnosis of UA/NSTEMI confirmed ADMIT + UA/NSTEMI confirmed Outpatient follow-up Evaluate for Reperfusion ST ? Stress study to provoke ischemia prior to discharge or as outpatient

54 INITIATION OF ATHEROCLEROSIS

55 TYPES OF PLAQUES Lumen Lipid Core Fibrous Cap Media
- T-Lymphocyte - Macrophage - Foam cell - Activated intimal SMC “Vulnerable” Plaque “Stable” Plaque Lumen Lipid Core Fibrous Cap

56

57 PATHOGENESIS Molecular Basis
Normally a fine balance exists between production of collagen by smooth muscle cell & break down Impaired gene expression disturbs this balance

58 PATHOGENESIS OF ACS

59 TRIGGERS OF PLAQUE RUPTURE
Vulnerable Plaque Inflammatory infiltrate Thin fibrous cap Plaque Lumen Large lipid core Spontaneous or triggered rupture Non occlusive thrombus Occlusive thrombus

60 Non occlusive thrombus Occlusive thrombus
Factors limiting thrombosis Factors favoring thrombosis Minor plaque disruption High flow fibrinolytic activity Major plaque disruption Vasospasm low flow fibrinolytic activity Procoagulant state, such as fibrinogen, factor VII platelet ractivity Silent Unstable angina Non-Q-wave MI Sudden death Q-wave MI Sudden death

61 ACUTE CORONARY SYNDROME
Triggering activities of patients Acute Risk Factors of an Arterial Pressure surge or Vasoconstriction lead to Plaque Disruption Acute Risk Factors of a coagulability Increase or Vasoconstriction lead to complete occlusion by Thrombus Minor Plaque Disruption Non-Occlusive Thrombus Occlusive Thrombus Non-Vulnerable Atherosclerotic Plaque Vulnerable Atherosclerotic Plaque Myocardial Infarction or Sudden Cardiac Death Asymptomatic Unstable Angina or Non-Q-MI Major Plaque Disruption Occlusive Thrombus

62 UNSTABLE PLAQUE

63 LARGE NON OCCLUDING THROMBUS DUE TO ENDOTHELIAL EROSION

64 NON OCCLUDING THROMBUS DUE TO PLAQUE RUPTURE

65 OCCLUSIVE THROMBUS DUE TO PLAQUE RUPTURE

66 HEALED PLAQUE

67 PLATELET PLUG FORMATION
ADP Epinephrine Thrombin Adhesion Collagen Arachidonic Acid release Release of ADP, serotonin Thromboxane A2 GP IIb/IIIa exposure Platelet aggregation GP IIb/IIIa receptor blockers Aspirin Ticlopidine / Clopidogrel

68 GP IIb/IIIa (quiescent) GP IIb/IIIa (activated)
Resting Platelet Activated Platelet

69 GP IIb/IIIa (activated)
Fibrinogen vWF R.G.D. Sequence Platelet

70 Competitive Antagonist (Integrilin, Aggrastat)
Activated Platelet

71 Fibrous Cap Disruption
Thrombotic Process — Pathophysiology Plaque Characteristics & Disruption Thrombus Lumen Fibrous Cap Lipid-Rich Core Thinning Fibrous Cap Disruption

72 Production of LMWH by depolymerization of unfractionated heparin
Native heparin Depolymerisation process LMWH Pentasaccharide sequence Semin Thromb. Hemost. 1993; 19 suppl. 1: 1-11

73 MODE OF ACTION OF HEPARIN AND LMWH

74

75

76 MODE OF ACTION OF ANTIPLATELET AGENTS
Vessel Wall Injury Cyclooxygenase TXA2 Arachidonic Acid PGH2 TXA2 CLOPIDOGREL ADP ADP ASPIRIN Fibrinogen IIB IIIa GP IIb, IIIa ADP Receptor Platelet Platelet EC Lumen Vessel wall

77 ANTI-PLATELET THERAPY

78 Antiplatelet Agents GP IIb/IIIa Inhibitors
Fibrinogen GP IIb/IIIa Receptor Inhibitors

79 clopidogrel bisulfate
Oral Antiplatelet Agents Mechanism of Action clopidogrel bisulfate ADP dipyridamole ticlopidine HCl ADP phosphodiesterase ADP Collagen Thrombin TXA2 Gp IIb/IIIa Activation (Fibrinogen Receptor) COX TXA2 aspirin ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199–209.

80 Anticoagulants Direct Thrombin Inhibitors Hirudin-Thrombin Binding
Mechanisms of Thrombin Inhibition Fibrin Binding Site Fibrin Fibrin Catalytic Site ATIII/ Heparin Thrombin Thrombin Thrombin Substrate Recognition Site Hirudin

81 The Management of Patients with Acute Myocardial Infarction
Initial Assessment and Evaluation

82 Algorithm for Initial Assessment and Evaluation of the Patient with Acute Chest Pain
Chest pain consistent with coronary ischemia Within 10 minutes • Initial evaluatioon • 12 lead ECG • Establish IV • Aspirin mg - chewed • Establish continuous ECG monitoring • Blood for baseline serum cardiac markers Therapeutic/Diagnostic tracking according 12-lead ECG ECG suggestive of ischemia - T wave inversion or ST depression Nondiagnostic / normal ECG ST segment elevation or new bundle branch block

83 Patient presents to ED lobby
Emergency Department Algorithms/Protocol for Patients with Symptoms and Signs of AMI Onset of symptoms Ambulance presents patient to ED lobby Patient presents to ED lobby ED triage or charge nurse triages patient • AMI symptoms and signs • 12-lead ECG • Brief, targeted history Emergency nurse initiates emergency nursing care in acute care area of ED • Cardiac monitor • Blood studies • Oxygen therapy • Nitroglycerin • IV D5W • Aspirin Emergency Physician evaluates patient • History • Physical exam • Interpret ECG AMI patient?

84 Candidate for fibrinolytic therapy
Emergency Department Algorithms/Protocol for Patients with Symptoms and Signs of AMI AMI patient? Yes No Uncertain Candidate for fibrinolytic therapy Evaluate further Trans Mural Consult Yes Conduct education and follow-up instruction Fibrinolytic therapy No Other indicated treatment: • Other drugs for AMI (beta-blockers, heparin, aspirin, nitrates) • Transfer to cath lab for PTCA or surgery for CABG Admit Release

85 Patient with Acute Chest Pain with non-diagnostic and normal ECG
Non-diagnostic / normal ECG • Continue evaluation/monitoring in Emergency Department or Chest Pain Unit • Serial serum cardiac marker levels - CKMB, Trop • Serial ECGs • Consider noninvasive evaluation of ischemia • Consider alternative diagnoses No Evidence of MI or ischemia MI or demonstrable ischemia Discharge with follow-up as appropriate (Goal: hours) Admit to unit of appropriate intensity

86 Patient with Acute Chest Pain with T-wave inversion or ST depression
ECG suggestive of ischemia - T wave inversion or ST depression Differential diagnosis ischemia acute posterior MI ventricular hypertrophy digoxin effect pericarditis pulmonary embolus LBBB hyperventilation anxiety normal variants • Anti-ischemia Therapy • Analgesia Admit to unit of appropriate intensity Admission blood work • CBC • Electrolytes, BUN, creatinine • Lipid profile

87 Management of Patients with Non-ST Elevation MI
ST depression/T-wave inversion: Suspected AMI Assess Clinical Status Heparin + Aspirin Nitrates for recurrent angina High-risk patient: 1. Recurrent ischemia 2. Depressed LV function 3. Widespread ECG changes 4. Prior MI Clinical stability Antithrombins: LMWH - high-risk patients Anti-Platelets: GpIIb/IIIa inhibitor Catheterization: Anatomy suitable for revascularization Patients without prior beta-blocker therapy or who are inadequately treated on current dose of beta-blocker Persistnet symptoms in patients with prior beta-blocker therapy or who cannot tolerate beta-blockers Continued observation in hospital Consideration of stress testing Yes No Establish adequate beta-blockade Add calcium antagonist PCI CABG Medical Therapy Modified from Antman EM. Atlas of Heart Disease, VIII; 1996

88 Patient with Acute Chest Pain with ST elevation or new bundle branch block
ST segment elevation or new bundle branch block Assess suitability for reperfusion • ? Contraindications for fibrinolysis • Availability and appropriateness of primary angioplasty Initiate anti-ischemia therapy • Beta-blocker • Nitroglycerine Analgesia Admission blood work Initiate fibrinolysis if indicated Goal: 30 minutes from entry to ED Primary PTCA if available and suitable Goal: PTCA within 90 30 minutes Admit - CCU

89 The Management of Patients with Acute Myocardial Infarction
Initial Management

90 Management of Patients with ST Elevation
Aspirin Beta-blocker  12 h > 12 h Eligible for fibrinolytic therapy Fibrinolytic therapy contraindicated Not a candidate for reperfusion therapy Persistent symptoms ? No Yes Fibrinolytic therapy Primary PTCA or CABG Other medical therapy: ACE inhibitors ? Nitrates Anticoagulants Consider Reperfusion Therapy Modified from Antman EM. Atlas of Heart Disease, VIII; 1996

91 Comparison of Approved Fibrinolytic Agents
Streptokinase Anistreplase Alteplase Reteplase Dose MU mg mg 10U x in min in 5 min in 90 min over 30 min Bolus administration NO Yes No Yes Antigenic Yes Yes No No Allergic reactions Yes Yes No No (mostly hypotension) Systemic fibrinogen Marked Marked Mild Moderate depletion 90-min patency rate ~50% ~65% ~75% ~75% TIMI-3 flow % % % % Mortality rate % % % % Cost /dose (US) $ $ $ $2196

92 ContraindicatIons and Cautions for Fibrinolytic Used in Myocardial Infarction
Absolute Contraindications: Previous hemorrhagic stroke at any time: other strokes or cerebrovascular events within one year Known intracranial neoplasm Active internal bleeding (does not include menses) Suspect aortic dissection

93 ContraindicatIons and Cautions for Fibrinolytic Used in Myocardial Infarction
Cautions / Relative Contraindications Severe uncontrolled HTN on presentation (BP >180/110 mmHg) History of prior CVA or known intra-cerebral pathology not covered in contraindications Current use of anticoagulants in therapeutic doses (INR  2-3); no bleeding diathesis Recent trauma (within 2-4 weeks) including head trauma Noncompressible vascular punctures Recent (within 2-4 weeks) internal bleeding For streptokinase/anistreplase: prior exposure (especially within 5d-2 yrs) or prior allergic reaction Pregnancy Active peptic ulcer History of chronic hypertension

94 Primary Percutaneous Transluminal Coronary Angioplasty Recommendations
Class I Recommendations 1. As an alternative to fibrinolytic therapy if: ST segment elevation or new or presumed new LBBB Within 12 hrs of symptoms or > 12 hrs of persistent pain In a timely fashion (90  30 min) By experienced operators In appropriate environment 2. In cardiogenic shock patients < 75 yrs or within 36 hrs of AMI and revascularization can be performed within 18 hrs of onset of shock Class IIa Recommendations 1. As reperfusion strategy in candidates for reperfusion who have contraindications to fibrinolytic therapy

95 Primary Percutaneous Transluminal Coronary Angioplasty Recommendations
Class IIb Recommendations 1. In patients with AMI who do not present with ST elevation but who have reduced (< TIMI grade 2) flow of the infarct-related artery and when angioplasty can be performed within 12 hrs of onset of symptoms Class III Recommendations 1. This classification applies to patients with AMI who: undergo elective angioplasty in the non-infarct-related artery at the time of AMI are beyound 12 hrs after the onset of symptoms and have no evidence of myocardial ischemia have received fibrinolytic therapy and have no symptoms of myocardial ischemia are fibrinolytic-eligible and are undergoing primary angioplasty by and unskilled operator in a laboratory that does not have surgical capability

96 Advantages of Fibrinolytic Therapy
More universal access Shorter time to treatment Greater clinical trial evidence of: reduction in infarct size improvement of LV function Results less dependent on physician experience Lower system costs

97 Advantages of Primary PTCA
Higher initial reperfusion rates Lower recurrence rates of ischemia / infarction Less residual stenosis Less intracranial bleeding Defines coronary anatomy and LV function Utility when fibrinolysis contraindicated

98 Pharmacologic Management of Patients with MI Heparin Recommendations
Class I Recommendations 1. In patients undergoing percutaneous or surgical revascularization Class IIa Recommendations 1. Intravenously in patients undergoing reperfusion therapy with alteplase/reteplase (note change in recommendations) Bolus Dose 60 U/kg 70 U/kg Maintenance ~12 U/kg/hr ~15 U/kg/hr Maximum U bolus None U/h if >70kg aPTT x control x control (50-70 sec) for 48 hrs (50-70 sec) for 48 hrs

99 Pharmacologic Management of Patients with MI Heparin Recommendations
Class IIa Recommendations (continued) 2. Intravenous unfractionated heparin (UFH) or low molecular weight heparin (LMWH) subcutaneously for patients with non-ST elevation MI 3. Subcutaneous UFH (eg, 7,500 U b.I.d.) or low molecular weight heparin (eg, enoxaparin 1 mg/kg b.I.d.) in all patients not treated with fibrinolytic therapy who do not have a contraindication to heparin. In patients who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus), intravenous heparin is prefered 4. Intravenously in patients treated with nonselective fibrinolytic agents (streptokinase, anistrplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus)

100 Pharmacologic Management of Patients with MI Heparin Recommendations
Class IIb Recommendations 1. In patients treated with nonselective fibrinolytic agents, not at high risk, subcutaneous heparin, 7,500 U to 12,500 U twice a day until completely ambulatory Class III Recommendations 1. Routine intravenous heparin within 6 hrs to patients receiving a nonselective fibrinolytic agent (streptokinase, anistrplase, urokinase) who are not at high risk for systemic embolism

101 Pharmacologic Management of Patients with MI GP IIb/IIIa Inhibitors - New Recommendations
Class IIa Recommendations 1. For use in patients experiencing an MI without ST segment elevation who have some high-risk features and/or refractory ischemia, provided they do not have a contraindication due to a bleeding risk

102 Classification of Inotropic Agents
Agent Mechanism Inotrpic Vascular Effect Major Use Isoproterenol -1 receptor Dilatation Hypotension due tobradycardia; no pacing available Dobutamine -1 receptor Mild dilatation Low output with SBP >90 mm Hg Dopamine Low dose: Renovascular dilatation Hypoperfusion with SBP <90 mm Hg (dopaminergic) or 30 mm Hg below usual value Medium dose: (-1 receptor) Constriction High dose: (-receptor) Intense constriction Norepinephrine - receptor Intense constriction Extreme hypotension despite dopamine use Amrinone PDE inhibitor Dilatation Second-tier agent after failure of dopamine / dobutamine Milrinone PDE inhibitor Dilatation Digitalis Inhibts Na+-K Variable Established systolic LV dysfunction pump and symptoms of heart failure for chronic therapy

103 The Management of Patients with Acute Myocardial Infarction
Hospital Management

104 Sample Admitting Orders
Condition Serious IV NS or D5W to keep vein open Vital signs q 1/2 hr until stable, the q 4 hrs and p.r.n. Notify if HR <60 or >110; BP <90 or >150; RR <8 or >22. Pulse oximetry x 24 hrs Activity Bed rest with bedside commode and progress as tolerated after approximately 12 hrs Diet NPO until pain free, then clear liquids. Progress to a heart - healthy diet Medications Nasal O2 2 L/min x 3 hrs Enteric-coated aspirin daily (165 mg) Stool softener daily Beta-adrenoreceptor blockers Consider need for analgesics, nitroglycerin, anxiolytic

105 Heart-Healthy Diet complex carbohydrates = 50-55% of kilocalories
unsaturated fats ( 30% of kilocalories) foods high in: potassium (eg. fruits, vegetables, whole grains, dairy products) magnesium ( eg. green leafy vegetables, whole grains, beans, seafood) fiber (eg. fresh fruits and vegetables, whole-grain breads, cereals)

106 Treatment Strategy for Right Ventricular Ischemia/Infarction
Maintain right ventricular preload Volume loading (IV normal saline) Avoid use of nitrates and diuretics Maintain AV synchrony (AV sequential pacing for symptomatic high-degree heart block unresponsive to atropine) Prompt cardioversion for hemodynamically significant SVT Inotropic support Dobutamine (if cardiac output fails to increase after volume loading)

107 Treatment Strategy for Right Ventricular Ischemia/Infarction
Reduced right ventricular afterload with LV dysfunction Intra-aortic balloon pump Arterial vasodilators (sodium nitroprusside, hydralazine) ACE inhibitors Reperfusion Fibrinolytic agents Primary PTCA CABG (in selected patients with multivessel disease)

108 Clinical Profile of Mechanical Complications of Myocardial Infarction
Variable Ventricular Free Wall Paillary Muscle Septal Defect Rupture Rupture Age (mean, years) Days post MI Anterior MI 66% 50% 25% New Murmur 90% 25% 50% Palpable thrill Yes No Rare Previous MI 25% 25% 30% Echo: 2-D Visualize defect May have PE Flail or prolapsing leaflet Doppler Detect shunt Regurgitating jet in LA PA catheterization Oxygen step up Equalization of Prominent V-wave in Hi RV diastolic pressure PCW tracing Mortality: Medical 90% 90% 90% Surgical 50% Case report 40-90% Modified from Labovitz AJ, et al. Cardiovasc Rev Rep ; 5-948

109 The Management of Patients with Acute Myocardial Infarction
MI Management Summary

110 Initial Management in ED
Initial evaluation with 12-lead ECG in < 10 minutes targeted history (for AMI inclusion, thrombolysis exclusion) vital signs, focused examination Continual ECG, automated BP, HR monitoring IV access Draw blood for serum cardiac markers, electrolytes, magnesium, hematology, lipid profile panel

111 Initial Management in ED
Aspirin mg (chew and swallow) Sublingual NTG unless SBP <90 or HR <50 or >100: test for prinzmetal’s angina, reversible spasm, anti-ischemic, antihypertensive effects O2 by nasal prolongs, first 2-3 h in all; continue if PaO2 <90% Analgesia: small doses of morphine (2-4 mg) as needed Fibrinolysis or PCI if ST elevation > 1mV or LBBB (Goal: door-needle < 30 min or door-dilatation < min)

112 MI Management in 1st 24 Hours
Limited activity for 12 hours, monitor  24 hours No prophylactic antiarrhythmics IV heparin if: a) large anterior MI; b) PTCA; c) LV thrombus; or d) alteplase/reteplase use (for ~48 hours) SQ heparin for all other MI (7,500 u b.I.d.) Aspirin indefinitely IV NTG for hrs if no / HR or BP IV beta-blocker if no contraindications ACE inhibitor in all MI if no hypotension

113 In-Hospital Management
Aspirin indefinitely Beta-blocker indifinitely ACE inhibitor (DC at ~6 wks if no LV dysfunction) If spontaneous or provoked ischemia - elective cath Suspected pericarditis - ASA 650 mg q 4-6 hrs CHF - ACE inhibitor and diuretic as needed Shock - consider intra-aortic balloon pump + cath with PCI or CABG RV MI - fluids (NS) + inotropics if hypotensive

114 Predictors of 30 day Mortality in Fibrinolysis Patients GUSTO Trial - 41,021 patients
Heart rate 12% Other 10% (DM, smoking, BP; Height/Weight, Prior CVD; Time to Rx; Choice of fibrinolytic therapy; US hospital) AMI Location 6% Killip class 15% Systolic BP 24% Age 32% Circulation 1995; 91:

115 Clinical Indications of High Risk At Predischarge
Present Absent Absent Strategy I Strategy II Strategy III Submaximal Exercise Test at 5-7 Days Symptom-Limited Exercise Test at Days Markedly Abnormal Mildly Abnormal Negative Markedly Abnormal Mildly Abnormal Negative Exercise Imaging Study Exercise Imaging Study Reversible Ischemia No Reversible Ischemia Reversible Ischemia No Reversible Ischemia Strenuous Leisure Activity or Occupation Medical Treatment Symptom-Limited Exercise Test at 3-6 Weeks Markedly Abnormal Mildly Abnormal Negative Cardiac Catheterization Exercise Imaging Study Reversible Ischemia No Reversible Ischemia Medical Treatment

116 Recommendations for Hormone Replacement Therapy (HRT) After Acute MI
Class IIa Recommendations 1. HRT with estrogen and progestin for secondary prevention of coronary events should not be given de novo to postmenopausal women after AMI 2. Postmenopausal women who are already taking HRT with estrogen plus progestin at the time of AMI can continue their therapy HERS Study: JAMA 1998;280:605-13

117 Initial Treatment A = Aspirin and Antianginal therapy
B = Beta-blocker and Blood pressure C = Cigarette smoking and Cholesterol D = Diet and Diabetes E = Education and Exercise

118 Algorithm for the Evaluation and Management of Patients Suspected of Having an ACS.
Symptoms Suggestive of ACS Noncardiac Diagnosis Chronic Stable Angina Possible ACS Definite ACS Treatment as indicated by alternative diagnosis See ACC/AHA/ACP Guidelines for Chronic Stable Angina No ST elevation ST elevation Nondiagnostic ECG Normal Initial serum cardiac markers ST and/or T wave changes Ongoing pain Positive cardiac markers Hemodynamic abnormalities No recurrent pain; Negative follow-up studies Observe Follow-up at 4-8 hours; ECG, cardiac markers Stress study to provoke ischemia Consider evaluation of LV function if ischemia present (Test may be performed prior to discharge or as outpatient) Evaluation for reperfusion therapy Recurrent ischemic pain or positive follow-up studies Diagnosis of ACS confirmed Negative: Potential diagnoses: nonischemic discomfort low-risk ACS Positive: Diagnosis of ACS confirmed See ACC/AHA Guidelines for Acute MI Arrangement for outpatientfollow-up Admit to hospital Manage via acute ischemia pathway

119 III. Hospital Care A. Anti-ischemic Therapy
B. Antiplatelet and Anticoagulation Therapy C. Risk Stratification D. Early Conservative vs. Invasive Strategies

120 Acute Ischemic Pathway
Aspirin Beta-blockers Nitrates Antithrombin regimen GP IIb/IIIa inhibitor Monitoring (rhythm and ischemia) Recurrent Ischemia and/or ST segment shift, or Deep T-wave Inversion, or Positive cardiac markers Early Invasive strategy Early Conservative strategy Immediate angiography 12-24 hour angiography Recurrent symptoms/ischemia Heart failure Serious arrhythmia Patient stabilizes Evaluate LV function Stress Test EF < .40 EF  .40 Low risk Not low risk Follow on Medical Rx

121 A. Anti-Ischemic Therapy Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection in patients with ongoing rest pain 2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms 3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present 4. A beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, in the absence of contraindications

122 A. Anti-Ischemic Therapy Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection in patients with ongoing rest pain 2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms 3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present 4. A beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, in the absence of contraindications

123 A. Anti-Ischemic Therapy Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection in patients with ongoing rest pain 2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms 3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present 4. A beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, in the absence of contraindications

124 B. Antiplatelet and Anticoagulation Therapy
When platelets are activated, the GP IIb-IIIa receptor undergoes a change in configuration that results in binding of fibrinogen to platelet receptors, resulting in platelet aggregation. The efficacy of GP IIb-IIIa antagonists in prevention of the complications associated with percutaneous coronary intervention (PCI) has been documented in numerous trials, many of which were composed entirely or in large part of patients with UA.

125 B. Antiplatelet and Anticoagulation Therapy Class III Recommendations
Intravenous Thrombolytic Therapy in Non-ST Elevation MI

126 D. Early Conservative Versus Invasive Strategies Class I - Recommendations
1. An early invasive strategy is recommended in patients with UA/NSTEMI and any of the following high-risk indicators: Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemia therapy Elevated TnT or TnI New or presumed new ST-segment depression at presentation Recurrent angian/ischemia with CHF symptoms, an S3 gallop, pulmonary edema, worsening rales, or new or worsening mitral regurgitation.

127 D. Early Conservative Versus Invasive Strategies Class I - Recommendations
High-risk findings on noninvasive stress testing Depressed LV systolic function (eg.ejection fraction [EF] <0.40 on noninvasive study). Hemodynamic instability or angina at rest accompanied by hypotension. Sustained ventricular tachycardia. PCI within 6 months. Prior CABG

128 IV. Coronary Revascularization
Recommendations for Revascularization with PCI and CABG in Patients with UA/NSTEMI

129 Recommendations for Revascularization Class I - Recommendations
1. CABG for patients with significant left main CAD 2. CABG for patients with 3-vessel CAD; the survival benefit is greatest in patients with abnormal LV function (EF <0.50) 3. CABG for patients with 2-vessel CAD with significant proximal left anterior descending CAD and wither abnormal LV function (EF <0.50) or demonstrable ischemia on noninvasive testing

130 Recommendations for Revascularization Class I - Recommendations
4. PCI or CABG for patients with 1- or 2- vessel CAD without significant proximal left anterior descending CAD but with a large area of viable myocaridum and high-risk criteria on noninvasive testing 5. PCI for patients with multivessel CAD with suitable coronary anatomy, with normal LV function, and without diabetes

131 Recommendations for Revascularization Class I - Recommendations
6. CABG with the internal mammary artery for patients with multivessel CAD and treated diabetes mellitus 7. Intravenous platelet GP IIb/IIIa inhibitor in UA/NSTEMI patients undergoing PCI

132 Unstable Angina - Definition
angina at rest (> 20 minutes) new-onset (< 2 months) exertional angina (at least CCSC III in severity) recent (< 2 months) acceleration of angina (increase in severity of at least one CCSC class to at least CCSC class III) Canadian Cardiovascular Society Classification Agency for Health Care Policy Research

133 Unstable Angina pathogenesis
Plaque disruption Acute thrombosis Vasoconstriction

134 Unstable Angina pathogenesis
Plaque disruption Passive plaque disruption soft plaque with high concentration of cholesteryl esters and a thin fibrous cap Active plaque disruption macrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture

135 Unstable Angina pathogenesis
Acute Thrombosis Vulnerable plaque disrupted plaque with ulceration occurring in 2/3 of unstable patients the exposed lipid-rich core abundant in cholesteryl ester is highly thrombogenic Systemic Hypercoagulable State disrupted plaque with erosion occurring in 1/3 of unstable patients

136 Unstable Angina pathogenesis
Vasoconstriction the culprit lesion in response to deep arterial damage or plaque disruption area of dysfunctional endothelium near the culprit lesion platelet-dependent and thrombin-dependent vasoconstriction, mediated by serotonin and thromboxane A2

137 Acute Coronary Syndrome
Process of resolution spontaneous thrombolysis vasoconstriction resolution presence of collateral circulation Delayed or absence of resolution may lead to non-Q-wave or Q-wave myocardial infarction

138 Non-Q-Wave MI clues to diagnosis
Prolonged chest pain Associated symptoms from the autonomic nervous system nausea, vomiting, diaphoresis Persistent ST-segment depression after resolution of chest pain

139 Prinzmetal’s Angina clues to diagnosis
Transient ST-segment elevation during chest pain Intermittent chest pain often repetitive usually at rest typically in the early morning hours rapidly relieved by nitroglycerine Syncope (rare), Raynaud’s, migraine

140 Unstable Angina Anti-thrombotic Therapy
Thrombolytics are not indicated “lytic agents may stimulate the thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction” TIMI IIIB Investigators Circulation 1994; 89:

141 Recommendations for Revascularization Class I - Recommendations
Discharge prescription details

142 Fiban incidence of intracranial bleeding
Treatment (%) Study Compound Placebo Active Heparin RESTORE Tirofiban EPIC Abciximab 0.4 EPILOG Abciximab IMPACT II Integrelin Bolus Bolus + Infusion Low dose High dose The EXCITE Trial Investigators

143 Unstable Angina Anti-platelet Therapy
Summary The question is no longer “Is there a reason to use GP IIb/IIIa inhibitors?” but “Is there a reason not to use them?” Eric Topol, MD

144 Unstable Angina Anti-coagulant Therapy
Heparin recommendation is based on documented efficacy in many trials of moderate size meta-analyses (1,2) of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleeding titrate PTT to 2x the upper limits of normal 1. Circulation 1994;89:81-88 2. JAMA 1996;276:

145 Unstable Angina Anti-coagulant Therapy
Low-molecular-weight heparin advantages over heparin: better bio-availability higher ratio (3:1) of anti-Xa to anti-IIa activity longer anti-Xa activity, avoid rebound induces less platelet activation ease of use (subcutaneous - qd or bid) no need for monitoring

146 Unstable Angina Anti-coagulant Therapy
Low-molecular-weight heparin ESSENCE Trial (Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study) at 30days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin N Eng J Med 1997;337:

147 MITI: Mortality, Infarct Size, and Time
P=0.04 P<0.001 Percent Lecture Notes The MITI (Myocardial Infarction Triage and Intervention) trial examined the effect of prehospital- versus hospital-initiated fibrinolytic therapy on clinical outcome. The primary endpoint was a ranked composite score (death, stroke, serious bleeding, and infarct size). The relationship between time to treatment and outcome also was assessed. Patients treated within 70 minutes of symptom onset, or the “very early” group, had improved outcomes compared with patients who received later treatment (composite score, P=0.009; 30-day mortality, 1.2% vs 8.7%, P=0.04; infarct size, 4.9% vs 11.2%, P<0.001; ejection fraction, 53% vs 49%, P=0.03, respectively). (Weaver et al, 1993) Thus, very early treatment was associated with a more than 50% reduction in infarct size. Adapted from Weaver WD, et al. JAMA. 1993;270:

148 Door-to-Balloon Time (minutes)
Importance of Door-to-Balloon Time: 30-Day Mortality in the GUSTO-IIb Cohort P=0.001 Mortality (%) Lecture Notes A similar correlation between increased door-to-balloon time and increased mortality in primary PTCA-treated patients was also observed in the GUSTO-IIb cohort. (Berger et al, 1999) This cohort included 1,138 patients, of whom 565 were randomized to receive PTCA (those treated with t-PA were not included in the present analysis). The primary endpoint was 30-day mortality. Thirty-day mortality was lowest in the group treated within 60 minutes of presentation (1.0%), and steadily rose with increasing door-to-balloon interval. Logistic regression analysis revealed that time from enrollment to first balloon inflation was a significant predictor of mortality within 30 days; after adjustment for differences in baseline characteristics, the odds of death increased 1.6 times (P=0.008) for a movement from each time interval to the next. < > PTCA not performed Door-to-Balloon Time (minutes) Berger PB, et al. Circulation. 1999;100:14-20.

149 Patency and Mode of Reperfusion
90-minute patency Lecture Notes Based on the open-artery hypothesis, reperfusion must be early, full, and sustained to achieve improved outcomes from reperfusion therapy.This daigram combines these concepts. The graph demonstrates the speed and degree of patency achieved with fibrinolytic therapy versus percutaneous transluminal coronary angioplasty (PTCA). If fibrinolytics are administered 30 minutes after arrival in the ER (thick line), then patency rates are 62% at 30 minutes after administration, 74% at 45 minutes, and 84% at 90 minutes after administration. In contrast, for PTCA (thin line)—with a door-to-balloon time of 120 minutes—the ultimate 90-minute patency rate is higher at 93%, although in some intermediary periods fibrinolytic patency rates exceed those of PTCA. Thus, while the ultimate patency rate is higher for PTCA, there is a time before PTCA is performed when a pharmacologic approach opens more arteries. In the future, it may be possible to combine the speed of a pharmacologic approach with the definitive and sustained opening provided by PTCA. ED arrival Drug administration Time (minutes) Adapted from Gibson CM. Ann Intern Med. 1999;130:

150 ED Time Point 3: DECISION
The Four Ds Time of Onset ED Time Point 1: DOOR ED Time Point 2: DATA ED Time Point 3: DECISION ED Time Point 4: DRUG Time Interval III Decision to drug Time Interval II ECG to decision to treat Time Interval I Door to ECG Lecture Notes In an effort to reduce the time from symptom onset to the initiation of fibrinolytic therapy, the National Heart Attack Alert Program (NHAAP) has identified four critical and recordable time points, called “the four Ds.” These are identified as: Door (Time Point 1): The patient arrives at the emergency department (ED). Data (Time Point 2): An initial electrocardiogram (ECG) is obtained. Decision (Time Point 3): A decision is made to initiate fibrinolytic therapy. Drug (Time Point 4): Fibrinolytic therapy is initiated. The intervals between these time points were designated intervals I through III for the purpose of identifying and reducing in-hospital delays in treatment. NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997:

151 ACC/AHA Guidelines for the Management of Patients With AMI
ST-segment elevation Aspirin, beta-blocker, antithrombin 12 h >12 h Eligible for fibrinolytic therapy Fibrinolytic therapy contraindicated Not a candidate for reperfusion therapy Persistent symptoms? therapy Primary PTCA or CABG No Yes Other medical therapy: ACE inhibitors? Nitrates Consider reperfusion therapy Lecture Notes Prompt recanalization of an infarct-related artery by fibrinolytic therapy or mechanical means and consequent restoration of myocardial perfusion have been shown to limit infarct size, reduce mortality, and improve left ventricular function. Delay in treatment is a critical factor in decreasing overall survival. The delay may be patient-related (ie, delay in seeking treatment) or due to the time required for diagnosis and initiation of treatment. This slide presents a suggested schema for the management of AMI with ST-segment elevation. PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; ACE, angiotensin-converting enzyme. Adapted from Ryan TJ, et al. ACC/AHA 1999 Update. Available at and Accessed February 2000.

152 Summary: Importance of Early Treatment
Prompt reperfusion limits myocardial necrosis, preserves left ventricular function, and reduces mortality Achievement of early, complete reperfusion may be more feasible with fibrinolytic therapy than with primary PTCA Maximal benefits of fibrinolytic therapy are attained within the first hour of symptom onset, although benefits extend out to 12 hours Continued efforts are needed to minimize door-to-drug time Lecture Notes In patients with AMI, prompt reperfusion of the infarct-related artery limits myocardial necrosis, preserves left ventricular function, and reduces the risk of mortality. According to the open-artery hypothesis, reperfusion must be early, full, and sustained to attain optimal outcomes. The achievement of these goals may be more feasible with fibrinolytic therapy than with primary PTCA. Unlike PTCA, fibrinolytic therapy is more universally available and may be initiated in a more timely fashion, allowing greater opportunities for restoration of flow within 1 hour of patient presentation. Data from large-scale trials such as GISSI-I and MITI have demonstrated that the largest reduction in mortality is achieved when fibrinolytic therapy is initiated within approximately 1 hour of symptom onset. The LATE trial and others demonstrated beneficial effects on outcomes when treatment was administered up to 12 hours after symptom onset. However, every effort should be made to minimize the time to treatment.

153 Myocardial Infarction
Overview Estimated ,000 sudden (out-of-hospital) deaths per year in U.S. Approximately 1 million hospitalizations per year in U.S. Absolute number of MI events and fatality rates declining Remains principal cause of death in Western world

154 Acute MI Impact of Modern Critical Care on Mortality Defibrillation
Hemodynamic Monitoring b-Blockers Aspirin Thrombolysis PTCA Adapted from Antman, Braunwald In:Braunwald ed. Heart Disease p 1184.

155 Management of Acute MI Diagnosis Risk Stratification Acute Therapy
Reperfusion Adjunctive Complications Pre-Discharge Management

156 Diagnosis of Acute MI History
Classic symptoms: intense, oppressive chest pressure radiating to left arm Other symptoms: chest heaviness, burning radiation to jaw, neck, shoulder, back, arms nausea, vomiting diaphoresis dyspnea lightheadedness Symptoms may be mild or subtle

157 Diagnosis of Acute MI Physical Examination Tachycardia or bradycardia
Extrasystoles S3 or S4, mitral regurgitation murmur Lung rales Hypertension or hypotension Pallor, distress

158 Diagnosis of Acute MI Electrocardiogram
Defines location, extent, and prognosis of infarction ST elevation diagnostic of coronary occlusion Q-waves do NOT signify completed infarction ST depression or T inversion: unlikely total coronary occlusion ST elevation in RV4 for RV infarction Observe up to 24 hrs for non-diagnostic ECG Differentiate from early repolarization in V1-2

159 Acute MI Myocardial Enzymes CPK Troponin Gore et al. AJC 1987;59:1234.
Ohman et al. NEJM 1996;335:1333.

160 Diagnosis of Acute MI Echocardiography Not diagnostic, but supportive
Identify regional wall motion abnormalities Absence of contralateral wall hyperkinesia suggests multivessel disease or IRA recanalization Assess LV function, prior infarcts More sensitive than ECG for RV infarction

161 Differential Diagnosis
Diagnosis of Acute MI Differential Diagnosis Ischemic Heart Disease angina, aortic stenosis, hypertrophic CMP Nonischemic Cardiovascular Disease pericarditis, aortic dissection Gastrointestinal esophageal spasm, gastritis, PUD, pancreatitis, cholecystitis Pulmonary pulmonary embolism, pneumothorax, pleurisy

162 Diagnosis of Acute MI Coronary Angiography
May be necessary for equivocal symptoms and ECG e.g. patients with prior CABG, previous MI, myocarditis with diffuse ECG D’s, non-characteristic D’s on ECG Finding of acutely-occluded vessel diagnostic Allows mechanical reperfusion

163 Acute MI Coronary Angiography
Incorporated in primary, rescue PTCA strategies If  ischemia, spontaneous or exercise-induced or complicated (CHF, arrhythmia) Controversial if uncomplicated MI Delineates anatomy but may potentiate unneeded revascularization Very low risk but appreciable cost Key prognostic indicator

164 Management of Acute MI Diagnosis Risk Stratification Acute Therapy
Reperfusion Adjunctive Complications Pre-Discharge Management

165 Acute MI - Risk Stratification
The GUSTO Pyramid - 30 Day Mortality Model HX CV Disease (0.4%) HTN (0.6%) Prior CABG (0.8%) Accel t-PA (0.8%) Smoker (0.8%) Weight (0.8%) Diabetes (1%) Time-to-Rx (1%) Age x Killip (1.3%) Height (1.1%) MI Location (6%) Prior MI (3%) Heart Rate (12%) Killip Class (15%) Systolic Blood Pressure (24%) Age (31%) Lee et al. Circulation 1995;91:

166 Acute MI - Risk Stratification
ECG Classification - GUSTO I Outcome Category Occlusion Site ECG 1-Year Mortality 1. Prox LAD before septal  ST V1-6, I, aVL 25.6% fasicular or BBB 2. Mid LAD before diagonal  ST V1-6, I, aVL 12.4% 3. Distal LAD beyond diagonal  ST V1-4 or 10.2% Diagonal in diagonal  ST I, aVL, V5-6 4. Moderate-to- proximal RCA  ST II, III, aVF and 8.4% large inferior or LCX V1, V3R, V4R or (post, lat, RV) V5-6 or R > S V1-2 5. Small inferior distal RCA or  ST II, III, aVF only 6.7% LCX branch

167 Acute MI - Risk Stratification
Ejection Fraction Mortality (2-Year) Gottlieb et al. Am J Cardiol 1992;69:

168 Acute MI - Risk Stratification
Hemodynamic Subgroups - Killip Class GISSI-1 (%) Killip Definition Incidence Control Lytic Class Mortality Mortality I No CHF II S3 gallop or basilar rales III Pulmonary edema (rales >1/2 up) IV Cardiogenic shock

169 Management of Acute MI Diagnosis Risk Stratification Acute Therapy
Reperfusion Adjunctive Complications Pre-Discharge Management

170 ISIS-2 Collaborative Group, Lancet 1988;2:349.
Aspirin in Acute MI ISIS-2 4300 4295 4300 4292 ISIS-2 Collaborative Group, Lancet 1988;2:349.

171 Aspirin in Acute MI Recommendations
Indicated in ALL patients with acute MI, except for true aspirin allergy (not intolerance) Initiate orally with chewable compound, at least 160 mg stat some data suggest first dose should be 650 mg to achieve full antiplatelet effect Continue 325 mg per day indefinitely

172 Heparin for Acute MI? Heparin- Allocated Control- Allocated
Odds Ratio & 95% C.I. Death t-PA 17/476 (3.6%) 20/468 (4.3%) SK/APSAC 28/402 (7.0%) 28/389 (7.2%) Aspirin 30/622 (4.8%) 29/609 (4.8%) No Aspirin 15/256 (5.9%) 20/248 (8.1%) Any Bleeding t-PA 114/476 (23.9%) 83/468 (17.7%) SK/APSAC 85/402 (21.1%) 56/389 (14.4%) Aspirin 141/622 (22.7%) 97/609 (15.9%) No Aspirin 58/256 (22.7%) 42/248 (16.9%) 0.43 0.36 0.5 1.0 1.5 2.0 2.5 Heparin Better Control Better Mahaffey, et al. AJC 77:551–6, 1996

173 Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.
T-PA and Heparin Angio 90 min 18 hrs 40 hrs 80 hrs 7 days +ASA +ASA +ASA +ASA +ASA Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.

174 Acute MI Heparin Intravenous heparin recommended with t-PA
(intial bolus 5000 U, infusion 1000 U/hr, adjust for weight < 50 kg) No clear data for benefit with streptokinase and increased bleeding Discontinue after 24 hrs, except for: atrial fibrillation recurrent ischemia anteroapical MI for CVA prophylaxis

175 Acute MI IV Heparin Optimal aPTT appears to be 50 to 70 seconds
Not indicated with streptokinase GISSI-2/Int’l and ISIS-3 SK+ASA=SK+ASA+SQ hep GUSTO-I SK+IV hep = SK+SQ hep  Risk (at higher levels) of ICB GUSTO-II

176 Adjunctive Therapy for Acute MI
Beta Blockers (Prior to Thrombolytic Era) Pooled Analysis - 7 Day Outcome > 29,000 Patients (26 Trials) p<0.02 p<0.02 p<0.05 -13% -20% -15% Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.47.

177 TIMI 2 Immediate vs Deferred Metoprolol
48% of patients eligible for randomization to beta blocker 10% discontinued due to hypotension or bradycardia TIMI Study Group. N Engl J Med 1989;320:618.

178 Beta Blockers in Acute MI
Pooled Analysis of Randomized Trials Study Agent N Mortality Odds Ratio & 95% CI 1 2 Control Better Rx Better ISIS-1 16,027 Atenolol During MI MIAMI 5,778 Metoprolol TIMI IIB 1,434 Metoprolol Norwegian 1,884 Timolol Post MI BHAT 3,837 Propranolol Hennekens et al. NEJM 1996;335:1660.

179 Beta Blockers in Acute MI
Recommendations IV to oral beta blocker therapy in patients without contraindications in first 24 hours Avoid early therapy in patients with bradycardia, hypotension, inferior MI, CHF, impaired LV function, AV block, asthma Continue treatment for at least 2-3 years

180 Adjunctive Therapy for Acute MI
ACE Inhibitors Outcome in “Megatrials” Total 85,064 Patients Mortality Reduction = 5 lives/1000 Rx’d p=0.57 p=0.02 p=0.03 27,442 27,382 9435 9460 5666 5679

181 ACE Inhibitors in Acute MI
Pooled Analysis of Randomized Trials Study Agent N Mortality Odds Ratio & 95% CI 1 2 ISIS-4 58,050 Captopril During MI GISSI-3 19,394 Lisinopril CONSEN II 6,090 Enalaprilat SAVE 2,231 Captopril Post MI AIRE 2,006 Ramipril TRACE 1,749 Trandolapril Rx Better Control Better Hennekens et al. NEJM 1996;335:1660.

182 Adjunctive Therapy for Acute MI
Magnesium LIMIT-2 ISIS-4 p < 0.05 p = NS Woods et al. Lancet 1992;339:1553. ISIS-4 Collab Group Lancet 1995;345:669.

183 Magnesium in Acute MI Summary
Mortality benefit of empiric Rx - conflicting results of randomized trials possibly due to late administration and low mortality in the ISIS-4 trial Correct low serum [Mg+2] Magnesium 1-2 gm bolus over 5 minutes may be definitive Rx for Torsade de Pointes or polymorphic ventricular tachycardia

184 Adjunctive Therapy for Acute MI
Calcium Channel Antagonists Agent N Odds Ratio & 95% CI Ca+2Ant Control 15.0% Nifedipine 13.0% 1358 10.8% Verapamil 13.3% 1775 13.5% Diltiazem 2466 Verapamil/ Diltiazem 4241 12.4% 13.4% 13.0% Pooled 13.3% 5599 1 2 Less Mortality More Mortality Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.52.

185 Management of Acute MI Diagnosis Risk Stratification Acute Therapy
Reperfusion Adjunctive Complications Pre-Discharge Management

186 Complications of Acute MI
Extension / Ischemia Arrhythmia Pericarditis Expansion / Aneurysm Acute MI RV Infarct Heart Failure Mechanical Mural Thrombus

187 Management of Acute MI Intra-Aortic Balloon Pump Counterpulsation
Decreases systemic afterload Increases diastolic aortic pressure Reduces myocardial oxygen demand Improves systemic / end-organ perfusion Variable effects on coronary perfusion

188 IABP in Acute MI Indications
Cardiogenic shock not quickly reversed (indication less firm for hemodynamic instability without shock) Acute MR or VSD Refractory myocardial ischemia Refractory ventricular arrhythmias Useful as a bridge to revascularization and for support during recovery of extensive “stunned myocardium”

189 Management of Acute MI Indications for Invasive Hemodynamic Monitoring
Right Heart Catheterization (Swan-Ganz Catheter) Severe or progressive CHF or pulmonary edema VSD or papillary muscle rupture Cardiogenic shock or progressive hypotension Hypotension unresponsive to fluid Rx Need for inotropic or IABP support RV infarction Refractory VT Tamponade

190 Acute MI - Recurrent Infarction / Ischemia
Pathophysiology In distribution of infarct vessel: IRA reperfusion, then reocclusion thrombus propogation, branch occlusion distal embolization reduced coronary perfusion pressure with severe residual IRA stenosis reduced collateral flow from stenosed artery At a distance: reduced collateral flow from IRA new coronary thrombus (hypercoagulable state) reduced systemic perfusion pressure increased myocardial oxygen consumption

191 Acute MI - Complications
Recurrent Ischemia / Infarction Prevention: Aspirin Beta blockers ACE inhibitors with low LVEF ? heparin with fibrin-specific lytics (reocclusion) Treatment: Pharmacologic (beta blockers, nitrates) IABP Urgent revascularization Repeat lytics (antibodies to SK)

192 Acute MI - CHF and Shock Pathophysiology
Extensive (or multiple) LV infarction(s) - systolic dysfunction Impaired relaxation, compliance due to infarction or ischemia - diastolic dysfunction Extensive RV infarction or ischemia VSD or acute severe MR Tamponade (w/ or w/o free wall rupture) Others e.g. critical valve stenosis or regurgitation, toxic-metabolic, sepsis, beta- or Ca+2-blocker overdose, pulmonary embolism, bowel ischemia

193 Forrester JS et al. NEJM 1976;295:1356 and 1404.
Acute MI - CHF and Shock Hemodynamic Subsets Subset PCWP CI Clinical Setting (mm Hg) (l/min) 1 < 18 > 2.2 asymptomatic 2 > 18 > 2.2 pulmonary congestion 3 < 18 < 2.2 RV failure, hypovolemia, or profound venodilation 4 > 18 < 2.2 severe LV dysfxn cardiogenic shock Forrester JS et al. NEJM 1976;295:1356 and 1404.

194 Acute MI - Cardiogenic Shock
Outcome with PTCA Pooled Analysis of 22 Retrospective Studies Historical control mortality ~ 80% Total 646 pts PTCA success rate = 76% Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 461.

195 Acute MI - Mechanical Complications
Free Wall Rupture Less frequent (1-3.4%), but earlier, with thrombolysis Uncontained  sudden EMD or asystole Pseudoaneurysm  transient hypotension, EMD, bradycardia, repetitive emesis, restlessness Echocardiogram usually diagnostic Surgical repair - may require pericardiocentesis for uncontained rupture

196 Acute MI - Mechanical Complications
Interventricular Septal Rupture Incidence 1-3% of transmural MIs Acute shock, pulmonary edema, right heart failure, new loud pan-systolic murmur (thrill in 50%) Diagnose with echocardiogram or O2 saturation step-up Medical stabilization and IABP for CHF, shock Early surgical repair for decompensated pts; mortality highest in pts with inferior MI and complex ruptures involving RV (~70%), lowest for apical ruptures (~30%) Small asymptomatic VSDs may not require repair

197 Acute MI - Complications
Infarct Expansion Potential consequences: LV aneurysm +/- mural thrombus +/- embolization adverse LV remodeling and CHF ventricular rupture ventricular arrhythmias Prevention: ACE inhibitors ? nitrates the “open artery”

198 Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445.
Acute MI The “Late Open Artery” n Time to Follow-Up Patent Occluded Angio IRA IRA (days) (months) Mortality Mortality Cigarroa % 18% Gohike 102 < % 17% Galvani % 17% White % 10% Lamas % 24% Welty 479 < % 17% Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445.

199 Acute MI - Mechanical Complications
Acute Mitral Regurgitation Transient MR common in early MI (20-40%) Associated with advanced age, prior MI, infarct extension, recurrent chest pain, CHF, female gender Persistent MR, even mild, associated with increased long-term mortality post-MI May be due to papillary muscle or chordal rupture or to geometric changes (dilation) of ventricle and annulus Most common with inferior MI (single blood supply to posteromedial papillary muscle) - MI often small

200 Acute Mitral Regurgitation
Diagnosis and Management harsh, short systolic murmur - may be muffled sudden CHF +/- hypotension or shock 2-7 days post MI echocardiography (surface or TEE) usually diagnostic - mobile papillary muscle head or flail MV leaflet LV function often normal or hyperkinetic sudden hemodynamic deterioration common stabilize medically, IABP, then surgical repair surgical mortality high if shock is present role of surgery in MR not due to rupture less clear

201 Acute MI - Complications
Right Ventricular Infarction Associated with occlusion of proximal RCA Classic triad by hypotension, JVP, clear lungs specific but insensitive Kussmaul’s sign, JVP > 8 cm H2O sensitive and specific EKG: ST in RV4 Echo: RV dilation and hypokinesia PA catheter: RA >10 mm, RA/PCWP ratio > 0.8

202 Acute MI - RV Infarction
Management Extensive irreversible infarction is unusual - transient ischemic dysfunction with long-term recovery common Marked by sensitivity to preload reduction (nitrates, diuretics, morphine), bradycardia, AV block Fluid volume infusion for hypotension and low cardiac output PCWP elevation may occur due to septal shift Dobutamine if fluids  RA and PCWP without improved BP and CI

203 Prophylactic Lidocaine
Acute MI - Arrhythmias Prophylactic Lidocaine Prophylactic use for suppression of VT or VF controversial Overview of randomized trials: 33% reduction in primary ventricular arrhythmias trend toward 38% increased mortality (asystole) Potential benefit in reperfusion era - GUSTO I (but not a randomized comparison) Should likely avoid unless VT / VF or non-sustained VT occurs

204 Acute MI - Antiarrhythmic Agents
Pooled Analysis of Randomized Trials Study Agent N Mortality Odds Ratio & 95% CI 0.1 1 10 CAST 1,498 Enc / Flec Class I CAST II 1,325 Moricizine EMIAT 1,486 Amiodarone CAMIAT 1,202 Amiodarone Class III SWORD 3,121 d-Sotalol Julian et al 1,456 l-Sotalol Rx Better Control Better NEJM 1996;335:1660. Lancet 1997;349:667 and 675.

205 Ventricular Tachycardia or Fibrillation
Acute MI - Arrhythmias Ventricular Tachycardia or Fibrillation Prognosis of VT or VF in first 48 hours controversial MILIS - no increased in-hospital mortality GISSI - increased in-hospital mortality No increased mortality after hospital discharge VT or VF after first 48 hours associated with poorer long-term prognosis Acute management - K+ replacement, antiarrhythmic therapy (lidocaine, procainamide, or amiodarone) if stable, electrical shock if unstable Long term management - pharmacologic therapy of unclear benefit, ICD may be beneficial

206 Acute MI - Arrhythmias Atrial Fibrillation
Incidence reduced with thrombolysis (<5%) Associated with large MI (especially if sustained) Prognostic of adverse events over following year Rate control with digoxin, or (without CHF) beta blockers, verapamil, or diltiazem Consider IV amiodarone Electrical cardioversion for hemodynamic compromise or ischemia

207 Indications for Temporary Pacing
Acute MI - Arrhythmias Indications for Temporary Pacing asystole complete (third-degree) AV block second-degree Mobitz II AV block second-degree Mobitz I AV block with hypotension new bifascicular block, esp with first-degree AV block symptomatic bradycardia, unresponsive to atropine Transcutaneous standby pacing for new LBBB, sick sinus syndrome with sinus pauses

208 Indications for Permanent Pacing
Acute MI - Arrhythmias Indications for Permanent Pacing persistent complete (third-degree) AV block persistent sinus node dysfunction - symptomatic bradycardia intermittent second-degree Mobitz II or third-degree AV block second-degree Mobitz II or third-degree AV block with new bundle branch block

209 Management of Acute MI Diagnosis Risk Stratification Acute Therapy
Reperfusion Adjunctive Complications Pre-Discharge Management

210 Pre-Discharge Management
Acute MI Pre-Discharge Management Risk stratification Catheterization and revascularization strategy Electrophysiologic evaluation for VT or VF Lifestyle modification: diet, exercise, tobacco Pharmacologic therapy

211 Acute MI - Risk Stratification
Post-MI Revascularization Strategy Low Risk High Risk* Nl LVSF  LVSF Nl LVSF  LVSF Stress Imaging or Catheterization Stress Imaging Direct Cath Normal Angiography Revascularization * (Re) MI or CP, VT, CHF, Prior MI, Prior Revascularization

212 Pharmacologic Therapy on Hospital Discharge
Acute MI Management Pharmacologic Therapy on Hospital Discharge Aspirin indefinitely (ticlopidine or clopidogrel for aspirin allergy or intolerance) Beta blockers for at least 2-3 years ACE inhibitors for CHF, LVEF<40%, or large infarction (even with preserved LVEF) Lipid lowering agents Coumadin for mural thrombus, extensive anterior infarct, DVT, atrial fibrillation

213 Thrombolysis in Acute MI
Relative Contraindications Uncontrolled HTN (BP > 180/110) on presentation History prior CVA beyond 1 yr Anticoagulant Rx with INR > 2-3; bleeding diathesis Recent trauma (within 2-4 wks) Noncompressible vascular punctures Recent internal bleeding (within 2-4 wks) Pregnancy Active peptic ulcer Prior exposure (5 day - 2 yr) for SK or APSAC

214 Thrombolysis in Acute MI
Absolute Contraindications Previous hemorrhagic stroke CVA within previous yr Intracranial neoplasia or AVM Active internal bleeding (not menses) Suspected aortic dissection

215 Myocardial Reperfusion
The Original Paradigm Re-establish Infarct Vessel Patency Limit Infarct Size  Mortality

216 Days from Randomization
GUSTO Mortality Trial Angiographic Trial 41,021 Patients 30-day Outcome 2,431 Patients TIMI 3 flow SK ( IV ) SubQ t-PA + Accel. t-PA 8 6 4 2 10 12 14 16 18 20 22 24 26 28 30 % Mortality Days from Randomization

217 Thrombolytic: Placebo-Control
Meta-Analysis Odds Agent Trial Name Deaths/Patients Odds Ratio Reduction Active Control (& 95% Cl) (± s.d.) Streptokinase GISSI 495/ / % ± 6 ISAM 50/842 61/868 16% ± 18 ISIS-2 471/ / % ± 5 APSAC AIMS 32/502 61/502 50% ± 16 t-PA ASSET 182/ / % ± 9 Overall: any thrombolytic 1230/ / % ± 3 Patients < 6 hours 8.7% 11.6% 0.0 0.5 1.0 1.5 2.0 Lytic better Lytic worse

218 Thrombolysis for Acute MI
Time to Therapy and Mortality Reduction Pooled Analysis of Randomized Trials Fibrinolytic Therapy Trialists. Lancet 1994;343:311.

219 New Fibrinolytics ASSENT II INTIME II p=0.003

220 Thrombolysis for Acute MI
Electrocardiographic Criteria for Therapy Pooled Analysis of Randomized Trials EKG Odds Ratio & 95% CI 0.33 1 3 Placebo Better Lysis Better Placebo Lysis 23.6% BBB 18.7% 16.9% ST Anterior 13.2% 8.4% ST Inferior 7.5% 13.4% ST Other 10.6% 13.8% ST 15.2% 5.8% Other Abnorm 5.2% 2.3% Normal 3.0% Fibrinolytic Therapy Trialists. Lancet 1994;343:311.

221 Thrombolysis and Age GISSI -1 and ISIS -2 GUSTO 1 N = 28,896 Patients
26% RR  D = 1.2% 14% RR  D = 2.4% D = 3.9% 6% RR  D =1.3% 17% RR  D = 1.0%

222 Acute MI PTCA vs Lysis 11 RCTs (2725 patients)
PCAT Collaborative Group, 2001

223 Primary Angioplasty in Acute MI
Pooled Analysis of Randomized Trials Trial PTCA Lysis N 2.0% Zijlstra 7.4% 389 Odds Ratio & 95% CI 0.1 1 10 Lysis Better PTCA Better SK Trials 9.3% Grinfeld 10.3% 112 6.5% DeWood 4.5% 90 2.6% PAMI 395 4.3% Gibbons 3.6% 103 0.0% Ribichini 2.4% 83 3.2% Elizaga 10.6% 189 5.7% GUSTO II 7.0% 1138 4.4% Pooled 2599 6.0% Ribeiro 100 t-PA Accel Pooled 32% RR Topol, Van de Werf. Textbook Cardiovasc Med 1998;p416

224 Acute MI: 1995 RESCUE 156 pts < 8 hours chest pain, ant. MI with occluded LAD PTCA successful in 92% of patients Outcomes at 30 Days

225 Pathophysiology of Combination Therapy in AMI
Reduces Reinfarction*  Thrombus  % Stenosis  Minimum Diameter  Myocardial Blush  ST Resolution There are compelling pathophysiologic reasons why combination therapy may benefit the management of acute MI. In Phase II angiographic trials, combination therapy has been shown to improve thrombus burden. This in turn has been related to improvements in both epicardial and microvascular coronary blood flow before and after percutaneous coronary intervention (PCI). Arteries were opened earlier and with better blood flow than with thrombolytic monotherapy. Another potential benefit of combination therapy may also lie in the ability of combination therapies to reduce thrombus burden and thereby reduce reinfarction rates. References Gibson CM, de Lomos JA, Murphy SA, et al. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy. Circulation. 2001;103: Gibson CM, Cannon CP, Piana RN, et al. Angiographic predictors of reocclusion after thrombolysis: results from the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. J Am Coll Cardiol. 1995;25:  Epicardial Flow Facilitates PCI  Myocardial Flow *Gibson et al. J Am Coll Cardiol. 1995;25: Gibson et al. Circulation. 2001;103:

226 Recent Clinical Trials
GP IIb/IIIa Receptor Inhibitor Trial Lytic Anticoagulant GUSTO-V 100% r-PA 50% r-PA None Abciximab Standard-dose heparin Low-dose heparin ASSENT-3 100% TNK-tPA 50% TNK-tPA None Abciximab ACC/AHA heparin dose Low-dose heparin Enoxaparin Several large clinical trials evaluating various agents have been published recently (GUSTO-V, ASSENT-3) and several other Phase II angiographic studies are due to be completed in the next few months (ENTIRE, INTEGRITI, FASTER). This presentation will critically examine the results and clinical implications of the GUSTO-V and ASSENT-3 trials and will review the trial designs of the ongoing trials. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: ENTIRE 50% TNK-tPA 100% TNK-tPA Abciximab None Unfractionated heparin Enoxaparin

227 Clinical Trials: Ongoing
GP IIb/IIIa Receptor Inhibitor Trial Lytic Anticoagulant FASTER 50% TNK-tPA 75% TNK-tPA 100% TNK-tPA Tirofiban Low-dose heparin INTEGRITI 50% TNK-tPA 75% TNK-tPA 100% TNK-tPA Eptifibatide Low-dose heparin Shown here are the treatment strategies in two of the recently completed Phase II trials involving combination therapy. The Fibrinolytic and Aggrastat ST Elevation Resolution (FASTER) trial is examining tenecteplase (TNK-tPA) in various doses (½, ¾, and full-dose) with tirofiban and low-dose heparin. The Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial is examining TNK-tPA in various doses (½, ¾, and full-dose) with eptifibatide and low-dose heparin.

228 GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality Reduction
60 54% 50 t-PA 6.3% 40 32% % TIMI Grade 3 Flow 30 Recently completed Phase II angiographic studies have utilized the incidence of TIMI Grade 3 flow as a surrogate end point. The value of TIMI Grade 3 flow as a surrogate end point for mortality was demonstrated in the GUSTO-I trial. The GUSTO-I angiographic investigators demonstrated that the 22% improvement in TIMI Grade 3 Flow at 90 minutes of recombinant tissue plasminogen activator over Streptokinase (SK) resulted in a 1.1% improvement in mortality. It has therefore been predicted that it would require a 20% improvement in the rate of TIMI Grade 3 flow to yield a 1% improvement in mortality. Thus, this trial satisfies the criteria for a surrogate mortality end point: TIMI Grade 3 flow is associated with improved mortality and changes in a reperfusion regimen that yield higher rates of TIMI Grade 3 flow are associated with a lower mortality. If current thrombolytic monotherapy regimens yield 54% to 60% rates of TIMI Grade 3 flow, then combination therapy would need to increase these rates to 74% to 80% to achieve a 1% reduction in mortality. References The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329: 20 SK 7.4% 10 t-PA SK 5 6 7 8 The GUSTO Angiographic Investigators. N Engl J Med. 1993;329:

229 % Patients With TIMI Grade 3 Flow
TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent Trials 100 Lytic alone Combination 80 78 73 73 70 64 60 56 56 54 54 % Patients With TIMI Grade 3 Flow 47 40 40 While data from the dose finding phases of these trials were quite encouraging, shown here is data from dose confirmation phases of various Phase II angiographic studies of combination therapy. Overall, there was an 8% difference improvement in TIMI Grade 3 Flow among patients treated with combination therapy in this pooled analysis. If a 20% improvement is required to improve mortality by 1%, then an 8% improvement might be anticipated to improve mortality by 8/20 of 1% or by about 0.4%. References The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329: Antman EM, Giuglano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 Trial. Circulation. 1999;99: The SPEED Study Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101: 20 292 63 58 87 88 98 100 81 75 329 321 GUSTO-I 90 min T14 t-PA 90 min T14 r-PA 90 min SPEED 60-90 min INTRO-AMI 60 min Pooled 60-90 min

230 SPEED: Results of Dose-Confirmation Phase
100 TIMI-2 There was a 7.4% improvement in the rate of TIMI Grade 3 flow If a 20% improvement is required to improve mortality by 1%, then a 7.4% improvement would be predicted to improve mortality by 0.3% TIMI-3 80 28.7 21.6 60 Patency (%) 54.9 47.5 40 The pilot study preceding the GUSTO-V trial was the SPEED trial. Shown here are the findings from the dose confirmation phase of the SPEED trial. There was a 7.4% improvement in the rate of TIMI Grade 3 Flow. Based upon the previous data from GUSTO-I, if a 20% improvement in TIMI Grade 3 flow yields a 1% improvement in mortality, a 7.4% improvement would be predicted to give a 7.4 / 20 or approximately a 0.3% improvement in mortality. Indeed, this was observed in the subsequent Phase III mortality trial, GUSTO-V, as demonstrated in the slides that follow. References The SPEED Study Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101: The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329: 20 n=109 n=115 r-PA U r-PA 5+5 U + Abx The SPEED Study Group. Circulation. 2000;101:

231 GUSTO-V: Study Design ST , lytic eligible, < 6 h (n=16,588)
ASA No Abciximab Abciximab 2 x 10 U bolus (30’) Full-dose r-PA 2 x 5 U bolus (30’) Half-dose r-PA Standard Heparin: 5000 U bolus followed by 800 U/h (< 80 kg) or U/h ( 80 kg) infusion Low-dose Heparin: 60 U/kg bolus followed by 7 U/kg/h infusion The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V trial was designed as a superiority trial to demonstrate that combination therapy was superior to standard AMI therapy. Full-dose r-PA plus standard unfractionated heparin (UFH) was compared with the combination of half-dose r-PA plus abciximab plus low-dose UFH in patients with ST-segment elevation AMI. About patients were required to detect a 15% relative mortality reduction from 7·4% to 6·3% with five interim analyses at 1000, 2500, 5000, 8300, and patients, and one final analysis with an overall alpha of 2·5% and 80% power with a one-sided 2 test. For noninferiority, the upper limit of the 95% CI (1.11) was calculated by indirect estimation of the preservation of at least 75% of the benefit of streptokinase over placebo. For the combination of half-dose reteplase and abciximab to be regarded as non-inferior, the upper bound of the 95% CI for the relative risk could be no greater than Interim analyses were reviewed by the Safety and Efficacy Monitoring Committee with the Lan-DeMets method of stopping criteria. All p values reported are two-sided, and analysis was by intention to treat. GUSTO-V was an open-label study that randomized patients to r-PA at the standard dose of two 10 U boluses given over 2 to 5 minutes at 30-minute intervals or combination therapy with half-dose r-PA (two 5 U boluses over 2 to 5 minutes at 30-minute intervals) plus abciximab (0.25 mg/kg bolus and µg/kg per min infusion [maximum of 10 µg/min]) for 12 hours plus half-dose r-PA (two boluses of 5 U given 30 minutes apart). All patients were administered aspirin (150 to 325 mg orally or 250 to 500 mg intravenously) at the time of randomization. Heparin administration was adjusted by a nomogram to achieve an activated partial thromboplastin time (aPTT) of between 50 and 70 seconds, but because abciximab has an anticoagulant effect, the dosing for heparin varied according to the treatment assignment. For patients treated with full-dose r-PA, the heparin dose was a 5000 U bolus followed by a 1000 U/h infusion for those patients weighing at least 80 kg (or an 800 U/h infusion for those weighing less than 80 kg). In the combination therapy arm, patients received a 60 U/kg heparin bolus (maximum 5000 U) followed by an infusion of 7 U/kg per hour. This heparin dose of 60 U/kg is low, but not as low as the 40U/kg that was assessed in some of the earlier dose finding pilot studies that preceded GUSTO-V. The primary end point of this study was mortality at 30 days, and the secondary end point was clinical and safety events at 30 days. Reinfarction and complications of AMI were recorded until only day 7 or hospital discharge. Inclusion criteria included the following: Continuous symptoms of chest discomfort for at least 30 minutes and no more than 6 hours from time onset to randomization ECG evidence of AMI with ST-segment elevation or new left-bundle branch block Exclusion criteria included the following: One blood pressure measurement higher than 180 mmHg systolic and 110 mmHg diastolic Weight >120 kg References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 1º end point: mortality at 30 days 2º end point: clinical and safety events at 30 days The GUSTO-V Investigators. Lancet. 2001;357:

232 Primary End Point: 30-Day Mortality
6 5.9% 5.6% 4 P=.43 for superiority % Mortality Non-Inferiority RR 0.95 (95% CI, ) 2 The primary end point of the GUSTO-V trial was all cause 30-day mortality by an intent to treat analysis. A statistical penalty was paid for the multiple interim looks at the data for the test of superiority (ie, the P-value required to achieve statistical significance was made more stringent, down to a P-value of .025). The mortality among r-PA monotherapy patients was 5.9% (n=8260) while it was 5.6% (n=8328) among patients treated with low-dose r-PA and full-dose abciximab (P=.43). Thus, combination therapy with low-dose r-PA along with full-dose abciximab was not superior to r-PA monotherapy (P=.43). References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: Std. Reteplase (n = 8260) Abx +  Dose Reteplase (n = 8328) 5 10 15 20 25 30 Days The GUSTO-V Investigators. Lancet. 2001;357:

233 GUSTO-V: Noninferiority Analysis
Upper Boundary of 95% CI for Noninferiority 1.11 OR and 95% CI Non-Inferiority RR 0.95 (95% CI, ) With the advent of improved adjunctive therapies in acute MI, mortality rates continue to slowly decline. Thus, achieving absolute reductions in mortality becomes increasingly difficult. In order to account for these recent reductions in absolute mortality rates in AMI trials, statistical analyses of data from AMI trials often now employ odds ratios (OR) rather than absolute differences. In the GUSTO-V trial, the OR for the difference between the 2 drugs was up to 1.08, which was within the upper boundary of the 95% confidence interval (CI)—or 1.11—that was prespecified for noninferiority. Thus, the combination of half-dose r-PA plus abciximab was “noninferior” to full-dose r-PA. A noninferiority analysis also preserves the ability to demonstrate superiority, if that is in fact observed. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 0.0 Abciximab + Half-dose r-PA superior 1.0 Full-dose r-PA superior 2.0 Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:

234 A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V Trials
8 50 48% 1.0 7.4% 0.91% 0.9 7 40 0.8 6 5.9% 37% 0.7 5 0.59% 30 0.6 4 0.5 20 0.4 3 0.3 2 Prior to the results of ASSENT-3 where the mortality was 5.4% for TNK-tPA plus enoxaparin, the 5.9% mortality for r-PA monotherapy was the lowest recorded to date in a major trial. However, as this slide demonstrates, the same drug may be associated with a different mortality in different trials depending upon the risk of the population studied. As has been well demonstrated in the past, anterior myocardial infarction is a major predictor of mortality in acute myocardial infarction (AMI). This slide demonstrates that the magnitude of the mortality difference for the same agent, r-PA monotherapy in GUSTO-V versus GUSTO-III trial, is directly proportional to the lower number of anterior MIs enrolled in GUSTO-V. These data again emphasize that the proportion of anterior MI patients enrolled is a major determinant of the overall mortality in a Phase III trial. Likewise, the rate of intracranial hemorrhage (ICH) was lower in GUSTO-V than in GUSTO-III, despite the fact that the same drug, r-PA monotherapy, was studied in both trials. This may reflect either the risk of the population or changes in concomitant drug administration such as heparin. References The GUSTO-III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337: The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 10 0.2 1 0.1 10,138 8,260 10,138 8,260 10,138 8,260 GUSTO III GUSTO V GUSTO III GUSTO V GUSTO III GUSTO V Death Anterior MI ICH The GUSTO-III Investigators. N Engl J Med. 1997;337: The GUSTO-V Investigators. Lancet. 2001;357:

235 GUSTO-V: Causes of Reinfarction
4 P<.0001 3.5 r-PA 3 r-PA + Abx 2.7 2.3 Myocardial Infarction (%) 2 1.7 1.6 1.2 The risk of reinfarction was reduced in the GUSTO-V trial. The specific type of reinfarction that was diagnosed is shown. As can be seen, the majority of the reinfarctions were classified as such on the basis of ischemic ST changes in the setting of acute MI. New Q-wave development was quite infrequent, as were creatine kinase (CK) release infarctions. The precise timing of reinfarction was also not clear. In particular, it is unclear if the reinfarctions occurred before PCI or as a complication of adjunctive PCI. Though there were more early PCIs in the monotherapy arm, if there are late PCIs in the combination therapy arm, these may be accompanied by CK release MIs. Indeed if PCIs were only performed later in the combination therapy arm (ie, if combination therapy only delayed PCI), these were not accounted for in the reinfarction data as the data were only collected to 7 days. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 1 0.5 0.2 Any Q-wave Enzymatic Ischemic ST Change* *Unblinded, unadjudicated The GUSTO-V Investigators. Lancet. 2001;357:

236 Non-Intracranial Bleeding Through Discharge/Day 7
30 25 r-PA 24.6 r-PA + Abx 20.0 20 % of Patients 15 13.7 11.4 10 Combination therapy of r-PA plus abciximab resulted in higher rates of bleeding and transfusion in the GUSTO-V trial. In patients of all ages, the overall risk of bleeding (24.6% vs 13.7%, P<.0001) and the need for transfusion (of both blood and platelets) was significantly increased with combination therapy (5.7% vs 4.0%, P<.0001). References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 5.7 10 3.5 4.0 1.8 1.1 0.5 Severe Bleeding Moderate Bleeding Mild Bleeding Any Bleeding Receiving Transfusions The GUSTO-V Investigators. Lancet. 2001;357:

237 ICH by Age Group % of Patients 3 2 1 r-PA (n=8260) r-PA + Abx (n=8328)
2.1 2 P=.53 1.5 % of Patients 1.2 1.1 1 In the GUSTO-V trial, the risk of ICH tended to be increased among patients over the age of 75 (2.1% vs 1.1%, P=.069). When a test of interaction was used to determine if there was a relationship between age and the effect of combination therapy on the rate of bleeding, the interaction term was significant (P=.033). This has raised concerns regarding the safety of combination therapy in the elderly. It also raises a question as to whether pharmacologic dosing should be both weight and age adjusted. A 40 U dose of heparin was also studied in the preceding SPEED pilot study, and the bleeding may have been lower with this dose than the 60 U dose that was studied in GUSTO-V. Lower adjunctive heparin dosing is being used in other ongoing combination therapy trials. The analysis of the data at over age 70 was prespecified while the analysis at over 75 years of age was not prespecified. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: P=.27* P=.66 0.5 0.4 0.4 0.3 24/6230 21/6193 25/2030 31/2135 37/7172 28/7179 12/1088 24/1149  70 yrs > 70 yrs  75 yrs > 75 yrs *Significant treatment interaction for the age 75 dichotomy; P=.033. The GUSTO-V Investigators. Lancet. 2001;357:

238 GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7
30 * 27.9 * 25.4 25 20 Urgent PCI (%) 15 Through Day 7 * Urgent PCI within the first 6 hours was performed in significantly fewer patients who received the combination of half-dose r-PA plus abciximab compared with those who received full-dose r-PA monotherapy. The rate of PCI within 6 hours was 8.6% in the full-dose r-PA group and 5.6% in the combination therapy group (half-dose r-PA plus abciximab group; P<.0001). At 7 days, the use of PCI was 27.9% and 25.4%, respectively (P<.0001). While combination therapy may reduce the rate of PCI, this may have worked against the combination therapy arm with respect to mortality. If adjunctive or rescue PCI reduces mortality and if an adjunctive / rescue PCI strategy was used less often in the combination therapy arm, this may have paradoxically offset the potential mortality benefit of combination therapy. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 10 8.6 * 5.6 5 r-PA r-PA + Abx *P<.0001. The GUSTO-V Investigators. Lancet. 2001;357:

239 GUSTO-V: Event Rates in Those Requiring Urgent PCI
12 r-PA n=1173 r-PA + Abx 10 9.6 9.0 8 6.7 Myocardial Infarction (%) 6 5.4 4.8 4 Although this reduced rate of PCI was viewed as encouraging, there was concern because, among the 1173 patients who underwent urgent PCI, mortality was slightly higher among those who received the combination half-dose r-PA plus abciximab, although this was not significant. The reason(s) for this higher rate in mortality is not clear and may have been due in part to a slightly higher risk profile among patients who were treated with combination therapy. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 2.8 2 Death Repeat MI Death Plus Repeat MI Heartwire News. September 2, GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?

240 GUSTO-V: Conclusions Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in A mortality rate that was not inferior to r-PA monotherapy Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation) A lower rate of urgent revascularization More noncerebral bleeding complications, transfusions, and thrombocytopenia A higher rate of ICH in elderly patients over the age of 75 years Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in: A mortality rate that was not inferior to r-PA monotherapy Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation) A lower rate of urgent revascularization More noncerebral bleeding complications, transfusions, and thrombocytopenia A higher rate of ICH in elderly patients over the age of 75 years References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:

241 ASSENT-3: Rationale for Use of Enoxaparin
TNK-tPA plus enoxaparin Favorable effects of LMWHs in recent small-scale thrombolysis trials Higher late patency: HART-2 ASSENT-Plus AMI-SK Less reocclusion: HART-2 Fewer reinfarctions: ASSENT-Plus AMI-SK Wilson, et al. ASSENT-3 is the first large-scale trial to test LMWH Shown here are some of the rationale for the use of Enoxaparin in acute MI. Angioscopy studies have shown that a large proportion of patients have persistent thrombus at the culprit stenosis up to one month following thrombolytic administration. The presence of thrombus is in turn associated with a higher risk of reinfarction. To this end, the antithrombotic agent enoxaparin may be effective in reducing reinfarction. Indeed, enoxaparin has been demonstrated to improve late patency and to lower reinfarction rates in several smaller preceding Phase I and II trials. In ASSENT-3, enoxaparin was given for up to a total of 7 days.

242 ASSENT-3: Study Design ST-Segment Elevation AMI (n=6095 patients)
150 to 325 mg ASA (daily) Randomized The Assessment of the Safety and Efficacy of a New Thrombolytic Therapy (ASSENT)-3 trial was designed to test TNK-tPA with three other agents (enoxaparin, abciximab, and UFH) to find the optimal pharmacologic reperfusion strategy for AMI. ASSENT-3 included over 6000 patients with ST-elevation MI who were randomized to 1 of 3 treatment groups: Full-dose TNK-tPA plus the low-molecular-weight heparin, enoxaparin, given up to discharge or revascularization with a maximum of 7 days Half-dose TNK-tPA plus the platelet GP IIb/IIIa receptor inhibitor, abciximab, for 12 h and low-dose UFH Full-dose TNK-tPA plus weight-adjusted UFH for 48 h according to the revised 1999 ACC/AHA guidelines. This was the first large trial to assess the ACC/AHA heparin dosing regimen. Inclusion criteria included the following: Symptom onset within 6 hours of randomization ECG evidence of AMI with ST-segment elevation Exclusion criteria included the following: Systolic BP >180 mmHg and/or diastolic BP >110 mmHg on repeated measurements. The dosing of the antithrombotic and antiplatelet therapy was as follows: Patients assigned weight-adjusted intravenous UFH received a bolus of 60 U/kg (maximum of 4000 U) and initial infusion of 12 U/kg per h (maximum 1000 U/h) adjusted to maintain an aPTT of s for 48 hours with subsequent heparin administration left to the discretion of the treating physician. The first blood sample for activated partial thromboplastin time measurement was drawn after 3 hours. Patients assigned enoxaparin combination therapy received an intravenous bolus of 30 mg immediately followed by the first subcutaneous dose of 1 mg/kg. This subcutaneous dose was repeated every 12 hours up to hospital discharge or revascularization with a maximum duration of therapy of 7 days. The first two subcutaneous doses could not exceed 100 mg. Patients assigned to abciximab combination therapy received 0.25 mg/kg bolus and g/kg/min (maximum of 10 g/min) for 12 h. Because abciximab has an anticoagulant effect, a lower dose of UFH was given: 40 U/kg bolus (maximum of 3000 U) followed by 7 U/h (maximum of 800U/h) to achieve a partial thromboplastin time between 50 and 70 s. Also in this group, the first aPTT was measured after 3 hours. Aspirin ( mg) was given to all patients. Intravenous boluses of UFH, enoxaparin and abciximab were to be given before the bolus of TNK-tPA. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: Full-dose TNK-tPA Plus Enoxaparin Half-dose TNK-tPA Plus Abciximab Plus Low-dose Heparin Full-dose TNK-tPA Plus Weight- adjusted UFH The ASSENT-3 Investigators. Lancet. 2001;358:

243 ASSENT-3: Primary End Points
Primary Efficacy End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia. Primary Efficacy Plus Safety End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia plus in-hospital intracranial haemorrhage or in-hospital major bleeding other than intracranial. The co-primary end points of ASSENT-3 are shown here: Primary Efficacy End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia. Primary Efficacy Plus Safety End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia plus in-hospital ICH or in-hospital major bleeding (other than intracranial bleeding). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:

244 ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia
3-way P=.0001 20 P=.0009* P=.0002* 15.4 15 11.4 11.1 % Risk of 30-Day D/MI/Ref Isch 10 Shown here are the results of the primary efficacy end point in a bar graph format. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy end point when the enoxaparin group was compared to the UFH group (P=.0009) and when the abciximab group was compared to the UFH group (P=.0002). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 5 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH *P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0002 for the enox vs UFH comparison, and P<.0001 for the abx vs UFH comparison.

245 % Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH
ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICH 3-way P=.0062 20 P=.0146* P=.0057* 17.0 15 14.2 13.8 % Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH 10 Shown here are the results of the primary efficacy and safety composite end point presented in a graphic format. When compared with full-dose TNK-tPA and UFH, full-dose TNK-tPA with enoxaparin and half-dose TNK-tPA with abciximab were associated with significant reductions in the efficacy plus safety composite end point (3-way P=.0062). For the comparison of full-dose TNK-tPA plus enoxaparin vs full-dose tenecteplase plus UFH, the P-value was P=.0037 for the primary efficacy and safety end point. For the comparison of half-dose TNK-tPA plus abciximab vs full-dose TNK-tPA plus UFH, the P-value was for the primary efficacy and safety end point. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy and safety end point at 30 days in the enoxaparin group (P=.0146) but not in the abciximab group (P=.057). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 5 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH *P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison.

246 Kaplan-Meier Curves Primary Efficacy Plus Safety End Point
Primary Efficacy End Point 20 20 18 18 UFH UFH 16 16 Abx 14 14 Enox* 12 12 Enox* Abx* Probability (%) 10 Probability (%) 10 8 8 6 6 Shown here are the data displayed as Kaplan-Meier Curves. The event rates separated early on after treatment within the first few days. This early divergence indicates that the benefit of enoxaparin was not simply due to its longer duration of administration. After correcting for multiple comparisons, statistical significance was reached for the TNK-tPA plus enoxaparin group in both the primary efficacy and primary efficacy plus safety end points, compared with the TNK-tPA plus UFH group. In patients treated with TNK-tPA combination therapy, statistical significance was reached for the primary efficacy end point but not the primary efficacy plus safety end point. Thus, the ASSENT-3 trial showed a significant early and sustained benefit in efficacy and safety for the TNK-tPA plus enoxaparin regimen. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 4 4 log-rank P=.0001 *vs UFH log-rank P=.0062 *vs UFH + Abx 2 2 5 10 15 20 25 30 5 10 15 20 25 30 Days to death, reinfarction, or refractory ischemia Days to death, reinfarction, refractory ischemia, ICH, or major bleeding Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:

247 % Risk of 30-Day Efficacy and Safety End Point
ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of Age 45 P=.001* 40 36.9 35 30 28.0 25.5 25 % Risk of 30-Day Efficacy and Safety End Point 20 15 This slide shows the results of the primary efficacy and safety end point among elderly patients over the age of 75. In patients over the age of 75, the risk of death/MI/refractory ischemia, ICH, or major bleeding was 25.5% for TNK-tPA plus enoxaparin, 36.9% for TNK-tPA plus abciximab, and 28% for TNK-tPA plus UFH. There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of 75 had poorer outcomes with abciximab (P=.001). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 10 5 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH *There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of 75 had poorer outcomes with abciximab (P=.001).

248 % Risk of 30-Day Efficacy and Safety End Point
ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with Diabetes 30 P=.007* 25 22.3 20 16.5 % Risk of 30-Day Efficacy and Safety End Point 15 13.9 10 This slide shows the results of the primary efficacy and safety end point among patients with diabetes. Among diabetic patients, the risk of death/MI/refractory ischemia, ICH, or major bleeding was 13.9% for TNK-tPA plus enoxaparin, 22.3% for TNK-tPA plus abciximab, and 16.5% for TNK-tPA plus UFH. There was a statistically significant interaction between treatment with abciximab and patients with diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 5 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH *There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007).

249 ASSENT-3: 30-Day Mortality
10 3-way P=.25 8 6.6 6.0 6 5.4 % Risk of 30-Day Mortality 4 The 30-day mortality rate among patients treated with TNK-tPA and enoxaparin was the lowest reported in a large scale trial to date. A 3-way P-value showed no statistically significant difference across the 3 arms in 30-day mortality. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

250 ASSENT-3: 30-Day Death or MI
10 3-way P=.0198 9.1 8 7.3 6.8 6 % Risk of 30-Day Death or MI 4 The enoxaparin arm was associated with the lowest rate of death or MI at 30 days (3-way P=.0198). References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

251 ASSENT-3: In-Hospital Recurrent MI
5 3-way P=.0009 4.2 4 3 2.7 % Risk of In-Hospital Recurrent MI 2.2 2 The enoxaparin and abciximab arms were associated with a lower rate of recurrent MI compared with the UFH arm. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 1 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

252 ASSENT-3: In-Hospital Refractory Ischemia
10 3-way P<.0001 8 6.5 6 % Risk of 30-Day Refractory Ischemia 4.6 4 The enoxaparin and abciximab arms were associated with a lower rate of refractory ischemia compared with the UFH arm. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 3.2 2 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

253 ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications
Enox Abx UFH P-Value (n=2040) (n=2017) (n=2038) 3-way Any thrombocytopenia <.0001 Thrombocytopenia <.0001 <20,000 cells/µL 20,000 to 50,000 cells/µL 50,000 to <100,000 cells/µL Bleeding episodes Total 25.6* <.0001 Major 3.0* Minor 22.6* <.0001 Blood transfusion 3.4* Significantly more major bleeding complications (P=.0002), more transfusions (P=.001), and a higher rate of thrombocytopenia (P=.0001) were observed in the abciximab group compared with the UFH group. In patients above 75 years and in patients with diabetes, the rate of major bleeding complications was three times as high in the abciximab group than in the UFH group: 13.3% vs 4.1% and 7.0% vs 2.2%, respectively. More major bleedings and blood transfusions were also observed in the enoxaparin group as compared with UFH but these differences were not statistically significant. References The Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 Investigators. Lancet. 2001;359 (In press). *While 3-way P-value is significant, Enox vs UFH comparison P=NS

254 ASSENT-3: In-Hospital Stroke Rates
Unclassified Hemorrhagic conversion Ischemic stroke* Intracranial hemorrhage Total strokes 0.15 0.07 0.40 0.64 0.94 0.88 1.49 1.62 Abx (n=2017) Enox (n=2040) 0.59 0.05 0.77 0.00 0.57 0.54 0.98 0.93 1.52 P-Value UFH (n=2038) Total stroke and intracranial hemorrhage rates were similar in the three groups. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: *Including hemorrhagic conversion

255 Patients Undergoing PCI: Mortality
8 ASSENT-3: In-Hospital PCI GUSTO-V: Urgent PCI 7 6.7 6 5.4 5 Mortality (%) 4 3.7 3 One of the goals of combination therapy was to improve outcomes following rescue/adjunctive PCI. Shown here are the mortality rates of patients undergoing either elective in-hospital PCI or urgent PCI with or without combination therapy. These nonrandomized data do not show a mortality benefit to the addition of abciximab to thrombolytic monotherapy, and in fact the mortality rates are slightly higher among patients treated with combination therapy. Patients treated with combination therapy may have had a greater number of comorbidities, and this may account in part for the observed results. The benefit of facilitated PCI with combination therapy requires further prospective evaluation. References The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2.7 2.5 2 1 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH r-PA + UFH r-PA + Abx

256 How Does Actual Weight Compare to Estimated Weight?
Correlation Between Estimated and Actual Patient Weight in TIMI 10B 188.5 R2=0.93, P<.0001 Actual Patient Weight (kg) TNK-tPA is dosed based upon estimated patient weight. Each dose category is 22 pounds wide. The patient does not need to be weighed; the weight can simply be estimated. Cannon et al have studied how the patient’s estimated weight compares to the actual weight. They found that the two were closely correlated as shown here. References Cannon CP, Gibson CM, Murphy SA, McCabe CH, Van de Werf F, Braunwald E. Weight-based dosing of thrombolysis: How well do we estimate weight? How often would this translate into errors with administration of thrombolytic drugs? A comparison of single-bolus TNK with t-PA in TIMI 10B. J Am Coll Cardiol. 2001;37:323A. 40.5 36.4 181 Estimated Patient Weight (kg) Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

257 Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight
Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? Errors in estimating weight are uncommon, especially those that would lead to a dose change (1.3% or 49/3730 for TNK-tPA and 4.5% or 13/290 for t-PA). No adverse outcomes were seen among patients who received an incorrect dose, suggesting a broad safety profile for the new single-bolus agent TNK-tPA. Errors in estimating weight are uncommon, especially those that would lead to a dose change (a 22 pound error occurred in 1.3% or 49/3730 cases for TNK-tPA and 4.5% or 13/290 for t-PA). No adverse outcomes were seen among patients who received an incorrect dose, suggesting a broad safety profile for the new single-bolus agent TNK-tPA. References Cannon CP, Gibson CM, Murphy SA, McCabe CH, Van de Werf F, Braunwald E. Weight-based dosing of thrombolysis: How well do we estimate weight? How often would this translate into errors with administration of thrombolytic drugs? A comparison of single-bolus TNK with t-PA in TIMI 10B. J Am Coll Cardiol. 2001;37:323A. Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

258 ASSENT-3: Study Group Conclusions Regarding TNK-tPA + Abciximab Therapy
“The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V.” “In both trials, these benefits are obtained at the cost of a higher rate of major bleeding complications and blood transfusions.” “No benefit and perhaps even harm was observed in patients above 75 years and in diabetics.” “Taken together they suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.” The conclusions of the ASSENT-3 study group regarding the combination of half-dose TNK-tPA plus full-dose abciximab are shown here. References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: The ASSENT-3 Investigators. Lancet. 2001;358:

259 ASSENT-3: Study Group Conclusions Regarding Enoxaparin
“In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase.” Lecture Notes With respect to the efficacy of enoxaparin, The ASSENT 3 Study Group concluded the following: “In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase.” References The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: The ASSENT-3 Investigators. Lancet. 2001;358:

260 ENTIRE TIMI-23: Study Design
ST  MI <6h (n=461) ASA Standard Reperfusion: Full-dose TNK-tPA (0.53 mg/kg) Combination Reperfusion: Half-dose TNK-tPA + Abx (0.27 mg/kg) The ENTIRE TIMI-23 trial was designed to assess the efficacy and safety of enoxaparin versus UFH as adjunctive antithrombin therapy either with full-dose TNK-tPA or with half-dose TNK-tPA in combination with intravenous abciximab. This was a Phase II open-label, angiographic trial conducted at 43 sites in 6 countries. 488 patients were randomized into one of the treatment regimens shown on this slide and were stratified by anterior versus nonanterior location of MI. The primary efficacy end point was TIMI Grade 3 flow at 60 minutes, and the primary safety end point was TIMI major hemorrhage at 30 days. The major secondary end points included ST segment resolution at 60 and 180 minutes and ischemic events through 30 days. Results of this study were presented at the European Society of Cardiology meeting held in Stockholm in September However, the results have not yet been published in the public domain. Source: Antman E, Gibson M, Heidbuchel H, et al. Enoxaparin with or without GP IIb/IIIa inhibition as reperfusion strategy in ST-segment elevation MI – results of the ENTIRE-TIMI 23 trial. Eur Heart J. 2001;22:15. Abstract 145. UFH 60 U/kg bolus 12 U/kg/h infusion  36 h ENOX varying doses +/- IV bolus Index Hosp ( 8 d)  UFH 40 U/kg bolus 7 U/kg/h infusion  36 h  ENOX varying doses +/- IV bolus Index Hosp ( 8 d) Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.

261 Outstanding Issues Should enoxaparin replace UFH as the optimal antithrombin agent for AMI? Will similar improvements in efficacy and safety occur if enoxaparin is combined with a less fibrin-specific agent such as r-PA? Will physicians accept the use of enoxaparin in selected patients with ST-elevation MI who may require rescue PCI? Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce results similar to ASSENT-3? What is the optimal strategy for facilitated PCI? Important questions remain: Should enoxaparin replace UFH as the ideal antithrombin agent for AMI? Fibrinolytic agents do not appear to be interchangeable, so will similar outcomes be observed if enoxaparin is combined with a less fibrin-specific agent such as r-PA? Will cardiologists accept the use of enoxaparin in patients with ST-elevation MI who may require rescue PCI? Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce similar or better results than ASSENT-3 and ENTIRE? What is the optimal strategy for facilitated PCI? All these questions require further evaluation in randomized prospective trials.

262 Future Trials: Potential Downstream Targets
Large embolii: Filters Small embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitors Vasoconstrictor release: GP IIb/IIIa inhibitors Spasm: Adenosine, Ca channel blockers, alpha blockers, avoid over sizing with PCI, high pressure inflations, serotonin inhibitors, endothelin inhibitors Endothelial & Myocardial swelling: Myocardial cooling, Ca channel blockers, DHEA, Na / H pump inhibitors, anti-inflammatory approaches The focus of acute MI therapy is beginning to shift from simple restoration of epicardial coronary artery blood flow to the restoration of tissue level perfusion. Potential downstream targets are shown on this slide.

263 Conclusions (cont.) Antiplatelet Agents — ASA & GP IIb/IIIa Blockers
ASA in treating ACS reduces relative risks of CVD/MI by 35%-50% GP IIb/IIIa blockers offer benefits in… CVD/MI/emergency revascularization: RRR up to 50% CVD/MI: RRR 10% to 27% Patients undergoing PTCA also have benefited from GP IIb/IIIa inhibitors Patients with acute MI may benefit from GP IIb/IIIa inhibition + thrombolysis ASA has reduced the relative risks of CVD/MI in treating ACS by about 35%-50%. Over 35,000 patients have participated in trials of parenteral GP IIb/IIIa inhibitors, which act on platelets to disrupt the final pathways leading to the creation and propagation of thrombi. RRRs at 30 days of up to 50% in CVD/MI/emergency revascularization have been observed; in CVD/MI RRRs range 10% to 27%. Patients undergoing percutaneous coronary interventions have benefited from GP IIb/IIIa therapy, and it recently has been used in combination with thrombolytics (alteplase) in treating MI with ST-segment elevation. [TIMI-14]

264 Conclusions (cont.) Anticoagulants — Indirect Antithrombins —
UFH & LMWH Antithrombin therapy treats acute exacerbation via short-term treatment UFH+ASA better than placebo or ASA alone in reducing CVD/MI/RA LMWH has clinical advantages over UFH, and is a useful agent early in treatment Since activation of thrombin is a key protagonist and amplifier of the hemostatic coagulation cascade, antagonism of thrombin would be expected to arrest the thrombogenic process. Antithrombin therapy treats an acute exacerbation via short-term treatment to prevent fatal and nonfatal MI. In patients with ACS receiving aspirin, research has indicated that the addition of indirect thrombin inhibitors — UFH or LMWH — is better than placebo at reducing rates of CVD, MI, and refractory angina. UFH has been the most widely used antithrombotic agent, however, it has a number of disadvantages that potentially limit its efficacy and it provides no inhibition of clot-bound thrombin. Combing UFH+ASA showed early, albeit nonsignificant, improvements over ASA alone in CVD/MI and recurrent ischemic attacks. [Oler meta-analysis] LMWH has a number of clinical advantages over UFH, and can be administered subcutaneously. Enoxaparin was found to be significantly superior to UFH — CVD/MI/RA RRR 10%, p 0.03 — with results persisting up to 43 days, and with no significantly increased risk of serious bleeding. [TIMI-11B + ESSENCE combined] Dalteparin (subcutaneous) was found to be an equivalent alternative for IV UFH, with benefits most pronounced during the acute phase and for higher risk patients. However, prolonged treatment did not confer added benefits. [FRISC and FRIC]

265 Conclusions (cont.) Anticoagulants — Direct Antithrombin - Hirudin
Studied internationally in 29,000+ patients Neutralizes clot-bound and soluble fibrin; no allergic reactions (lack of HIT) In acute MI, hirudin and UFH have equivalent effects as adjunctive therapy to thrombolysis In PTCA, hirudin is associated with fewer cardiac events compared to UFH In ACS, hirudin is superior to UFH: CVD/MI RRR 14% — 24% CVD/MI/RA RRR 19% — 22% Hirudin has been widely studied in trials including more than 29,000 subjects. It is a direct and potent antithrombin, and recent trials suggest that it may be more effective than indirect agents like UFH for treating ACS. Hirudin is able to neutralize clot-bound and soluble fibrin, and does not exhibit allergic reactions or HIT. In patients with acute MI, hirudin and UFH had equal effects as adjunctive therapy to thrombolysis. [TIMI-9B] In patients with UA undergoing PTCA, hirudin was associated with early, significant reductions in cardiac events compared to UFH. However, event-free survival at 30 weeks did not differ between treatment groups. [HELVETICA] In patients with ACS, hirudin (vs UFH) significantly reduced CVD/MI at 72hrs (RRR 24%, p=0.015). [OASIS-2] Benefits persisted at 7 days (RRR 19%, p= 0.039) and up to 35 days (RRR 14%, p = 0.04). [OASIS-1+OASIS-2 combined] Aggregate evidence supported these findings. [OASIS-1, OASIS-2, TIMI-9B, and GUSTO-2B combined] Also, absolute risk differences favoring hirudin were preserved over time. Results for CVD/MI/RA also showed an advantage of hirudin over UFH at 72hr (RRR 22%, p =0.019) and 7 days (RRR 19%, p =0.0125). [OASIS-2] In all studies, there were only modest additional risks of minor and major, non-life-threatening bleeds with hirudin, which were readily treatable. There was no excess in life-threatening bleeding events or cerebrovascular episodes compared to UFH.

266 Conclusions (cont.) Summary
Direct thrombin inhibition offers benefits over indirect thrombin inhibition for ACS Hirudin appears to be a safe, superior alternative to UFH Longer treatment durations need to be assessed for possible long-term benefits Combining a thrombin-specific inhibitor (eg, hirudin) with a GP IIb/IIIa blocker may be an even more effective antithrombotic therapy for ACS Comparisons of one clinical study to another examining different antithrombotic agents can be challenging due to unequivocal patient selection, endpoints, and follow-up periods. However, it appears that direct thrombin inhibition offers benefits over indirect thrombin inhibition. Recent clinical trials suggest hirudin is a safe, superior alternative to UFH for treating ACS. The observed benefits of hirudin occur primarily in the first 72 hours, and effects persist for up to 35 days. However, treatment durations in most of the current trials have been too short to assess possible long-term benefits of newer antithrombotic agents. Prolonged use of direct thrombin inhibitors may extend their benefits. Finally, a combination of the most potent antithrombin agent (eg, hirudin) and a GP IIb/IIIa inhibitor may potentiate antithrombotic therapy benefits in patients with ACS.

267 Comparative Advantages of Stress Echocardiography and Stress Radionuclide Perfusion Imaging in Diagnosis of CAD Advantages of Stress Echocardiography 1. Higher specificity 2. Versatility - more extensive evaluation of cardiac anatomy and function 3. Greater convenience / efficacy / availability 4. Lower cost Advantages of Stress Perfusion Imaging 1. Higher technical success rate 2. Higher sensitivity - especially for single vessel coronary disease involving the left circumflex 3. Better accuracy in evaluating possible ischemia when multiple resting LV wall motion abnormalities are present 4. More extensive published data base - especially in evaluation of prognosis

268 exercise time in minutes on Bruce Protocol
Prognostic Markers in Exercise Testing The Duke Treadmill Score (risk calculation) The Duke treadmill score = exercise time in minutes on Bruce Protocol minus 5x the ST-segment deviation (during or after exercise, in millimeters) 4x the angina index (“0” if there is no angina, “1” if angina occurs, and "2" if angina is the reason for stopping the test). works well for both inpatients and outpatients, and equally well for men and women N Engl J Med 1991;325:849-53

269 Survival According to Risk Groups Based on Duke Treadmill Score
4 -Year Annual Risk Group (Score) Total Survival Mortality Low ( +5) % 99% 0.25% Moderate (-10 to +4) 34% 95% 1.25% High (< -10) % 79% 5.00% N Engl J Med 1991;325:849-53

270 Risk Stratification With Coronary Angiography
the extent and severity of coronary disease and LV dysfunction are the most powerful clinical predictors of long-term outcome proximal coronary stenoses severe left main coronary artery stenosis CASS registry of medically treated patients, the 12-year survival rate Coronary arteries Ejection fraction normal coronary arteries 91% % to 100% 73% one-vessel disease 74% % to 49% 54% two-vessel disease 59% <35% 21% three-vessel disease 40% Circulation 1994;90:

271 Risk Factors for Coronary Artery Disease
Age: > 45 y/o male; > 55 y/o female; or post-menopausal female without estrogen therapy Male gender Hypertension Diabetes mellitus Hypercholesterolemia/Hypertriglyceridemia Smoking Family history of early CAD female age < 65; male age < 55 Past personal history of PVD or CVA

272 Risk Factors for Coronary Artery Disease (con’t)
Left ventricular Hypertrophy Cocaine/Ethanol Abuse Obesity Sedentary Lifestyle Oral contraceptives Homocysteine elevation Fibrinogen, C-reactive protein, Lp (a)

273 Guidelines to Reduce Risk For Patients With Coronary Disease and other vascular disease
Cessation of smoking Lipid Management Goals Primary Goal: LDL < 100 mg/dl Secondary: HDL > 35 mg/dl TG < 150 mg/dl Physical activity: 30 minutes 3-4 times per week Weight management Antiplatelet/anticoagulants:ASA 80 to 325 mg/day (or clopidogrel 75m/day) ACE inhibitors (post-MI for LVD) Beta blockers for high-risk patients post-MI Blood pressure control: goal < 130/85 mm Hg Adapted from Smith, Circulation 1995;92:3

274 Medical Therapy For Patients with CAD or Other Vascular Disease
Risk Reduction ASA % Beta Blockers % ACE inhibitors % Statins % The four medications every atherosclerosis patient should be treated with, unless contraindications exist and are documented Adapted from the UCLA CHAMP Guidelines 1994

275 TIMI IIIA Protocol Design 391 Patients with Unstable Angina / NQWMI
IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockers Angio Exclusion: no CAD or LMain Baseline Angio Randomize Placebo t-PA 0.8 mg/kg over 90 mins TIMI 3A evaluated 391 patients with unstable angina or non-Q wave MI with baseline coronary angiography and then randomized patients without left main CAD between treatment with tPA or placebo. F/U angiography was performed at hours to assess the effects of therapy on lesion severity. Primary Endpoint: Death, MI, Positive ETT 6 weeks Angio hrs Follow-up 6 weeks Circulation 1993;87:38-52 7 7 7

276 TIMI IIIA Primary Results Effects of tPA on Coronary Lesions
BASELINE ANGIORAPHY: Apparent thrombus No thrombus 35% 35% TIMI 3A angiographically evaluated 391 patients with unstable ischemic discomfort and documented CAD and found definite thrombus in only 35% or mural opacities/eccentric lesions classified as possible thrombus in 30%. Notably, this proportion of patients with visible thrombus was much lower than anticipated from prior reports. After randomization to therapy with either front-loaded tPA or placebo, angiography showed no difference in the degree of lesion improvement between the two treatment arms. Possible thrombus 30% ANGIORAPHY AFTER tPA: Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NS TIMI IIIA Investigators. Circulation 1993;87:38-52.

277 TIMI IIIB Protocol Design 1473 Patients with Unstable Angina / NQWMI
ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockers Randomize Early Conservative: ST Holter, ETT Thallium Cath/PTCA if +ischemia Early Invasive: Cath h PTCA/CABG prn 2x2 Factorial: t-PA vs. Placebo In light of the impressive benefits of thrombolytic therapy for ST elevation AMI and uncertainty regarding role and timing of invasive therapy for non-ST elevation acute coronary syndromes, TIMI 3B evaluated both of these therapeutic modalities for patients with unstable angina and non-Q wave MI. All 1473 patients received five-drug medical therapy with aspirin, intravenous heparin, beta-blockers (unless contraindicated), nitrates, and calcium antagonists (diltiazem) if clinically appropriate. Then, in a 2x2 factorial design patients were randomized to receive either tPA or placebo and to follow either an early invasive (routine angiography followed by PTCA if appropriate) or a conservative strategy (cardiac catheterization only if recurrent ischemia). The primary endpoint was a composite of death, post-randomization infarction, or documented recurrent ischemia through 6 weeks. 1o Endpoint Inv-Cons: Death, MI, Positive ETT - 6 weeks ETT 6 weeks 1o Endpoint t-PA: Death, MI, Rec Isch, + ETT, Thallium or ST Holter Circulation 1994;89: Follow-up 1 year 7 7 7

278 TIMI IIIB Investigators. Circulation 1994;89:1545-56
Primary Results tPA vs. Placebo in Non-ST Elevation ACS Composite Endpoint Death or MI ICH % of Patients Here we see the primary analysis of the efficacy of the tPA vs. placebo in TIMI IIIB. As depicted in the far left panel, there was no difference in the primary composite endpoint of death, post-randomization infarction, or documented recurrent ischemia through 6 weeks. Further, patients treated with tPA were at higher risk of death or MI (middle), as well as intracranial hemorrhage by 42 days (far right). P = NS P = 0.05 P = 0.05 TIMI IIIB Investigators. Circulation 1994;89:

279 TIMI IIIB Investigators. Circulation 1994;89:1545-56
Primary Results Early Invasive vs. Conservative Strategy Events at 42d Invasive Conservative p value No. Pts Death (%) NS MI (%) NS D/MI/+ETT (%) NS Rehosp Angina (%) <0.001 D/MI/Rehosp (%) LOS (days) <0.001 # Days rehosp <0.001 In the primary comparison of the early invasive vs. conservative strategies for management of non-ST elevation acute coronary syndromes in TIMI 3B, there was no difference in the composite outcome of death, post-randomization infarction or positive stress test at 6 weeks. Among patients following the invasive strategy, 61% underwent a revascularization procedure by 6 weeks. In comparison, by six weeks, 64% of those in the conservative arm had coronary angiography performed for recurrent angina at rest, or high risk results in non-invasive testing for ischemia leading to 49% having some form of revascularization. In reviewing secondary endpoints, we find a statistically significant reduction in the proportion of patients requiring re-hospitalization for recurrent angina in the invasive compared with the conservative strategy group. TIMI IIIB Investigators. Circulation 1994;89:

280 TIMI III REGISTRY Protocol Design
All consecutive patients admitted with unstable angina were screened. Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year. The TIMI 3 registry was designed to complement the TIMI IIIA and B trials with the goal of delineating the clinical profile and outcomes of all patients with non-ST elevation acute coronary syndromes. Over 9500 patients with ACS were screened and 3316 included in the registry.

281 TIMI III REGISTRY Risk Stratification
Admission ECG as a prognostic indicator ST deviation >0.1 mV _ LBBB Tw change No ECG changes 25 22.9 Death or MI 20 15 11 % of Patients 10 8.2 6.6 6.8 Among the 3316 patients with unstable angina and non-Q wave MI included in the TIMI III registry, the admission ECG was found to be a strong prognostic indicator with respect to the composite outcome of death or myocardial infarction. ST deviation in particular was associated with adverse outcomes at one year compared with those with no ST deviation whereas new T wave inversions did not add to the clinical history in predicting outcome. 3.6 3.7 3.7 5 2.6 1.6 1.6 0.8 In-Hospital 6 Weeks 1 Year Stone PH, TIMI III Registry Study Group. JAMA 1996;275: Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:

282 TIMI IIIB Risk Stratification cTnI to Predict Risk of Mortality in ACS
Enrolled 0-6 hrs Enrolled 6-24 hrs Enrolled 0-24 hrs P<0.001 P <0.05 P<0.001 1404 patients enrolled in TIMI 3B had baseline samples available for measurement of cardiac troponin I. This serum marker substudy from TIMI 3B demonstrated a near linear gradient of mortality risk with rising concentration of cTnI. This risk relationship persisted after multivariate adjustment for traditional clinical markers of cardiovascular risk. Further as depicted in this figure, cTnI was predictive of mortality at 6 weeks even among patients with normal CK-MB. Consistent with prior data regarding cardiac troponin T, the association between cTnI and mortality was not as strong among patients presenting early after symptom onset. However, for patients presenting over 6 hours after symptom onset, a negative cTnI correlated with low mortality risk. P <0.05 Antman et al. NEJM 1996; 335:1342-9

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