7 Comorbidity of Atherosclerotic Disease a major health burden Atherothrombosismajor complications of atherosclerosis are thrombosis, with local occlusion or distal embolizationCADCVAPADAronow WS, Ahn C. Am J Cardiol. 1994;74:64–65.
8 Endothelial Dysfunction Atherosclerosis Time-lineComplicatedLesion/RuptureFoamCellsFattyStreakIntermediateLesionAtheromaFibrousPlaqueAtherosclerosis 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 DysfunctionFrom FirstDecadeFrom ThirdDecadeFrom FourthDecadeAdapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).9
11 Overview of CAD Presentation Assessment of CAD likelihoodRisk stratification based on findingsAnti-ischemic drug therapyAnti-platelet/ anti thrombotic therapyInvasive versus conservative strategyPrimary 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 orderof importance, areNature of the anginal symptomsPrior history of CADSexAgeNumber of traditional risk factors presentThe 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 presentThe 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 markersHowever, the presence of these risk factors does appear to relate to poor outcomes in patients with established ACSDiabetes 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 reproduciblyassociated with physical exertion or emotional stressand is relieved promptly (in less than 5 min) withrest 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 nitroglycerinAtypical angina (probable) meets 2 of the of characteristicsNoncardiac chest pain meets 1 of the typical angina characteristicsJ Am Coll Cardiol. 1983;1:574, Letter
16 Differential Diagnosis of Prolonged Chest Pain AMIAortic dissectionPericarditisAtypical angina pain associate with hypertrophic cardiomyopathyEsophageal, other upper gastrointestinal, or biliary tract diseasePulmonary diseasepneumothoraxembolus with or without infarctionpleurisy: infectious, malignant, or immune disease-relatedHyperventilation syndromeChest wallskeletalneuropathicPsychogenic
17 Chest Pain Checklist Dr.Sarma@works YES Ongoing chest discomfort ( 20 min and < 12 hours)Oriented, can cooperateAge > 35 y (> 40 if female)ECG doneHigh-risk profile *Heart rate 100 bpmBlood pressure 100 mm HgPulmonary edema (rales > 1/2 way up)ShockNOHistory of stroke or TIAKnown bleeding disorderActive internal bleeding in past two weeksSurgery or trauma in past two weeksTerminal illnessJaundice, hepatitis, kidney failureUse of anticoagulantsSystolic/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/PMCheck 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 neededAdapted from the Seattle/King County EMS Medical Record
18 Acute Coronary Syndrome Ischemic Discomfort Unstable SymptomsHistory Physical ExamNo ST-segment elevationST-segment elevationECG(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 BiomarkersUnstable NSTEMI STEMI Angina (Non-Q MI) (Q-wave MI)(positive cardiac biomarker)
19 ACC/AHA Classifications Expert Opinion and Recommendations IIaIIbIIIIntervention is useful and effectiveEvidence conflicts/opinions differ but leans towards efficacyEvidence conflicts/opinions differ but leans against efficacyIntervention is not useful/effective and may be harmfulThe 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 effectiveClass II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatmentClass IIa weight of evidence/opinion is in favor of usefulness/efficacyClass IIb usefulness/efficacy is less well established by evidence/opinionClass 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 harmfulMost physicians would suggest that:Class I and IIa should be practicedClass IIb should be given careful consideration for an individual patient.Class III should not be practicedJACC 1999; Vol 33, No 7:
20 12 Lead Resting ECGshould be recorded in all patients with symptoms suggestive of angina pectorisnormal in 50% of patientsa 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 MIpersistent 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 prognosisLV hypertrophy by ECG criteria in a patient with angina pectoris is also associated with increased morbidity and mortalityA 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 tachyarrhythmiasAm J Cardiol 1982;49:
23 Risk stratification: Chest X-Ray often normal in patient with stable angina pectorisusefulness as a routine test is not well establishedfindings associated with poorer long-term prognosiscardiomegalyLV aneurysmpulmonary venous congestionleft atrial enlargementcalcium in the coronary arteries
24 Cardiac Troponins Advantages Disadvantages Clinical recommendations powerful tool for risk stratificationgreater sensitivity and specificity than CK-MBdetection of recent MI up to 2 weeks after onsetDisadvantageslow sensitivity in very early phase of MI (< 6 h after symptom onset)limited ability to detect late minor reinfarctionClinical recommendationsuseful 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 assaysability to detect early reinfarctionDisadvantagesloss of specificity in setting of skeletal muscle disease or injury, including surgerylow 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 recommendationsprior standard and still acceptable diagnostic test in most clinical circumstances
26 Myoglobin Advantages Disadvantages Clinical recommendations high sensitivityuseful in early detection of MIdetection of reperfusionmost useful in ruling out MIDisadvantagesvery low specificity in setting of skeletal muscle injury or diseaserapid return to normal range limits sensitivity for later presentationsClinical recommendationsshould 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 MICK-MB subform plus cardiac-specific troponin best combinationDo not rely solely on troponins because they remain elevated for 7-14 days and compromise ability to diagnose recurrent infarction
31 Enzymatic Criteria for Diagnosis of Myocardial Infarction Serial increase, then decrease of plasma CK-MB, with a change > 25% between any two valuesCK-MB > U/L or > 5% total CK activityincreasing MB-CK activity > 50% between any two samples, separated by at least 4 hrsif only a single sample available, CK-MB elevation > twofoldbeyond 72 hrs, an elevation of troponin T or I or LDH-1 > LDH-2
32 The Progressive Development of Cardiovascular Disease Risk FactorsEndothelial DysfunctionAtherosclerosisCADMyocardial IschemiaCoronary ThrombosisMyocardial InfarctionAtherosclerotic 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 MuscleRemodelingVentricular DilationCongestive Heart FailureEndstage Heart Disease10
33 Slide 3LThe 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
48 Risk Factors for Atherosclerotic Disease Non-modifiableAgeFamily historySexModifiableCigarette smokingDiabetes mellitusHyperlipidemiaHypertensionObesityPhysical inactivityHoeg JM. JAMA. 1997;277:1387–1390.
49 Vascular Endothelium Endothelium as an organ 1 to 6 x 1013 cells monolayerweighs 1 kgcovers 6 tennis courtsModulator of vascular tonenitric oxide (NO)prostaglandin I2 (PGI2, prostacycline)Regulator of hemostasisantithromboticprothromboticAnticoagulant:GAGs/AT IIITFPIThrombomodulinProfibrinolytic:t-PAu-PABinding sites for plasminogenPA receptorsPlatelet inhibitory:PGI2 (prostacycline)Nitric oxideADPaseCarbon monoxideProcoagulant:Tissue factorBinding sites for coagulation factors and fibrinAntifibrinolytic:PAITAFIPlatelet activating:vWFPAFFibronectinEndothelin-1TXA2AntithromboticVasodilationProthromboticVasoconstriction
50 ACUTE CORONARY SYNDROME No ST ElevationST ElevationNSTEMIUnstable AnginaNQMI QwMIMyocardial Infarction
53 ED MANAGEMENT OF UA/NSTEMI No recurrent pain;Neg follow-up studiesNondiagnostic ECGNormal serum cardiac markersObserveFollow-up at 4-8 hours: ECG, cardiac markersNeg: nonischemicdiscomfort;low-risk UA/NSTEMIYESNOST and/or T wave changesOngoing pain+ cardiac markersHemodynamic abnormalitiesRecurrent ischemic pain or+ UA/NSTEMI follow-up studiesDiagnosis of UA/NSTEMIconfirmedADMIT+ UA/NSTEMI confirmedOutpatient follow-upEvaluateforReperfusionST ?Stress study to provokeischemia prior to dischargeor as outpatient
59 TRIGGERS OF PLAQUE RUPTURE Vulnerable PlaqueInflammatory infiltrateThin fibrous capPlaqueLumenLarge lipid coreSpontaneous or triggered ruptureNon occlusive thrombusOcclusive thrombus
60 Non occlusive thrombus Occlusive thrombus Factors limiting thrombosisFactors favoring thrombosisMinor plaque disruptionHigh flowfibrinolytic activityMajor plaque disruptionVasospasm low flowfibrinolytic activityProcoagulant state, such as fibrinogen, factor VIIplatelet ractivitySilentUnstable anginaNon-Q-wave MISudden deathQ-wave MISudden death
61 ACUTE CORONARY SYNDROME Triggering activities of patientsAcute Risk Factors of an Arterial Pressure surge or Vasoconstriction lead to Plaque DisruptionAcute Risk Factors of a coagulability Increase or Vasoconstriction lead to complete occlusion by ThrombusMinor Plaque DisruptionNon-Occlusive ThrombusOcclusiveThrombusNon-Vulnerable Atherosclerotic PlaqueVulnerable Atherosclerotic PlaqueMyocardial Infarction or Sudden Cardiac DeathAsymptomatic Unstable Angina or Non-Q-MIMajor Plaque DisruptionOcclusiveThrombus
80 Anticoagulants Direct Thrombin Inhibitors Hirudin-Thrombin Binding Mechanisms of Thrombin InhibitionFibrin Binding SiteFibrinFibrinCatalyticSiteATIII/HeparinThrombinThrombinThrombinSubstrateRecognition SiteHirudin
81 The Management of Patients with Acute Myocardial Infarction Initial Assessmentand Evaluation
82 Algorithm for Initial Assessment and Evaluation of the Patient with Acute Chest Pain Chest pain consistent with coronary ischemiaWithin 10 minutes• Initial evaluatioon • 12 lead ECG • Establish IV • Aspirin mg - chewed • Establish continuous ECG monitoring • Blood for baseline serum cardiac markersTherapeutic/Diagnostic tracking according 12-lead ECGECG suggestive of ischemia - T wave inversion or ST depressionNondiagnostic / normal ECGST segment elevation or new bundle branch block
83 Patient presents to ED lobby Emergency Department Algorithms/Protocol for Patients with Symptoms and Signs of AMIOnset of symptomsAmbulance presentspatient to ED lobbyPatient presents to ED lobbyED triage or charge nurse triages patient• AMI symptoms and signs• 12-lead ECG• Brief, targeted historyEmergency nurse initiates emergencynursing care in acute care area of ED • Cardiac monitor • Blood studies • Oxygen therapy • Nitroglycerin• IV D5W • AspirinEmergency Physician evaluates patient• History • Physical exam • Interpret ECGAMIpatient?
84 Candidate for fibrinolytic therapy Emergency Department Algorithms/Protocol for Patients with Symptoms and Signs of AMIAMIpatient?YesNoUncertainCandidate for fibrinolytic therapyEvaluate furtherTrans MuralConsultYesConduct education and follow-up instructionFibrinolytic therapyNoOther indicated treatment:• Other drugs for AMI (beta-blockers, heparin,aspirin, nitrates)• Transfer to cath lab forPTCA or surgery for CABGAdmitRelease
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 diagnosesNo Evidence of MI or ischemiaMI or demonstrable ischemiaDischarge with follow-up asappropriate(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 depressionDifferential diagnosisischemiaacute posterior MIventricular hypertrophydigoxin effectpericarditispulmonary embolusLBBBhyperventilationanxietynormal variants• Anti-ischemia Therapy• AnalgesiaAdmit to unit of appropriate intensityAdmission blood work• CBC• Electrolytes, BUN, creatinine• Lipid profile
87 Management of Patients with Non-ST Elevation MI ST depression/T-wave inversion:Suspected AMIAssess Clinical StatusHeparin + Aspirin Nitrates for recurrent anginaHigh-risk patient: 1. Recurrent ischemia2. Depressed LV function3. Widespread ECG changes4. Prior MIClinical stabilityAntithrombins: LMWH - high-risk patients Anti-Platelets: GpIIb/IIIa inhibitorCatheterization: Anatomysuitable for revascularizationPatients without priorbeta-blocker therapy orwho are inadequatelytreated on current doseof beta-blockerPersistnet symptoms inpatients with priorbeta-blocker therapy orwho cannot toleratebeta-blockersContinued observationin hospitalConsideration ofstress testingYesNoEstablish adequatebeta-blockadeAdd calcium antagonistPCICABGMedicalTherapyModified 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 blockAssess suitability for reperfusion• ? Contraindications for fibrinolysis• Availability and appropriateness of primary angioplastyInitiate anti-ischemia therapy• Beta-blocker• NitroglycerineAnalgesiaAdmission blood workInitiate fibrinolysisif indicatedGoal: 30 minutesfrom entry to EDPrimary PTCAif available and suitableGoal: PTCA within90 30 minutesAdmit - 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 hEligible for fibrinolytic therapyFibrinolytic therapy contraindicatedNot a candidate for reperfusion therapyPersistent symptoms ?NoYesFibrinolytic therapyPrimary PTCA or CABGOther medical therapy: ACE inhibitors ? Nitrates AnticoagulantsConsider Reperfusion TherapyModified from Antman EM. Atlas of Heart Disease, VIII; 1996
91 Comparison of Approved Fibrinolytic Agents Streptokinase Anistreplase Alteplase ReteplaseDose MU mg mg 10U x in min in 5 min in 90 min over 30 minBolus administration NO Yes No YesAntigenic Yes Yes No NoAllergic reactions Yes Yes No No(mostly hypotension)Systemic fibrinogen Marked Marked Mild Moderatedepletion90-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 yearKnown intracranial neoplasmActive internal bleeding (does not include menses)Suspect aortic dissection
93 ContraindicatIons and Cautions for Fibrinolytic Used in Myocardial Infarction Cautions / Relative ContraindicationsSevere uncontrolled HTN on presentation (BP >180/110 mmHg)History of prior CVA or known intra-cerebral pathology not covered in contraindicationsCurrent use of anticoagulants in therapeutic doses (INR 2-3); no bleeding diathesisRecent trauma (within 2-4 weeks) including head traumaNoncompressible vascular puncturesRecent (within 2-4 weeks) internal bleedingFor streptokinase/anistreplase: prior exposure (especially within 5d-2 yrs) or prior allergic reactionPregnancyActive peptic ulcerHistory of chronic hypertension
94 Primary Percutaneous Transluminal Coronary Angioplasty Recommendations Class I Recommendations1. As an alternative to fibrinolytic therapy if:ST segment elevation or new or presumed new LBBBWithin 12 hrs of symptoms or > 12 hrs of persistent painIn a timely fashion (90 30 min)By experienced operatorsIn appropriate environment2. In cardiogenic shock patients < 75 yrs or within 36 hrs of AMI and revascularization can be performed within 18 hrs of onset of shockClass IIa Recommendations1. As reperfusion strategy in candidates for reperfusion who have contraindications to fibrinolytic therapy
95 Primary Percutaneous Transluminal Coronary Angioplasty Recommendations Class IIb Recommendations1. 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 symptomsClass III Recommendations1. This classification applies to patients with AMI who:undergo elective angioplasty in the non-infarct-related artery at the time of AMIare beyound 12 hrs after the onset of symptoms and have no evidence of myocardial ischemiahave received fibrinolytic therapy and have no symptoms of myocardial ischemiaare 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 accessShorter time to treatmentGreater clinical trial evidence of:reduction in infarct sizeimprovement of LV functionResults less dependent on physician experienceLower system costs
97 Advantages of Primary PTCA Higher initial reperfusion ratesLower recurrence rates of ischemia / infarctionLess residual stenosisLess intracranial bleedingDefines coronary anatomy and LV functionUtility when fibrinolysis contraindicated
98 Pharmacologic Management of Patients with MI Heparin Recommendations Class I Recommendations1. In patients undergoing percutaneous or surgical revascularizationClass IIa Recommendations1. 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 MI3. 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 prefered4. 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 Recommendations1. 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 ambulatoryClass III Recommendations1. 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 Recommendations1. 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 UseIsoproterenol -1 receptor Dilatation Hypotension due tobradycardia; no pacing availableDobutamine -1 receptor Mild dilatation Low output with SBP >90 mm HgDopamine 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 constrictionNorepinephrine - receptor Intense constriction Extreme hypotension despite dopamine useAmrinone PDE inhibitor Dilatation Second-tier agent after failure of dopamine / dobutamineMilrinone PDE inhibitor DilatationDigitalis 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 SeriousIV NS or D5W to keep vein openVital 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 hrsActivity Bed rest with bedside commode and progress as tolerated after approximately 12 hrsDiet NPO until pain free, then clear liquids.Progress to a heart - healthy dietMedications Nasal O2 2 L/min x 3 hrs Enteric-coated aspirin daily (165 mg) Stool softener daily Beta-adrenoreceptor blockersConsider 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 preloadVolume loading (IV normal saline)Avoid use of nitrates and diureticsMaintain AV synchrony (AV sequential pacing for symptomatic high-degree heart block unresponsive to atropine)Prompt cardioversion for hemodynamically significant SVTInotropic supportDobutamine (if cardiac output fails to increase after volume loading)
107 Treatment Strategy for Right Ventricular Ischemia/Infarction Reduced right ventricular afterload with LV dysfunctionIntra-aortic balloon pumpArterial vasodilators (sodium nitroprusside, hydralazine)ACE inhibitorsReperfusionFibrinolytic agentsPrimary PTCACABG (in selected patients with multivessel disease)
108 Clinical Profile of Mechanical Complications of Myocardial Infarction Variable Ventricular Free Wall Paillary Muscle Septal Defect Rupture RuptureAge (mean, years)Days post MIAnterior MI 66% 50% 25%New Murmur 90% 25% 50%Palpable thrill Yes No RarePrevious MI 25% 25% 30%Echo: 2-D Visualize defect May have PE Flail or prolapsing leaflet Doppler Detect shunt Regurgitating jet in LAPA catheterization Oxygen step up Equalization of Prominent V-wave in Hi RV diastolic pressure PCW tracingMortality: 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 minutestargeted history (for AMI inclusion, thrombolysis exclusion)vital signs, focused examinationContinual ECG, automated BP, HR monitoringIV accessDraw 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 effectsO2 by nasal prolongs, first 2-3 h in all; continue if PaO2 <90%Analgesia: small doses of morphine (2-4 mg) as neededFibrinolysis 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 hoursNo prophylactic antiarrhythmicsIV 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 indefinitelyIV NTG for hrs if no / HR or BPIV beta-blocker if no contraindicationsACE inhibitor in all MI if no hypotension
113 In-Hospital Management Aspirin indefinitelyBeta-blocker indifinitelyACE inhibitor (DC at ~6 wks if no LV dysfunction)If spontaneous or provoked ischemia - elective cathSuspected pericarditis - ASA 650 mg q 4-6 hrsCHF - ACE inhibitor and diuretic as neededShock - consider intra-aortic balloon pump + cath with PCI or CABGRV 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 PresentAbsentAbsentStrategy IStrategy IIStrategy IIISubmaximal Exercise Test at 5-7 DaysSymptom-Limited Exercise Test at DaysMarkedly AbnormalMildly AbnormalNegativeMarkedly AbnormalMildly AbnormalNegativeExercise Imaging StudyExercise Imaging StudyReversible IschemiaNo Reversible IschemiaReversible IschemiaNo Reversible IschemiaStrenuous Leisure Activity or OccupationMedical TreatmentSymptom-Limited Exercise Test at 3-6 WeeksMarkedly AbnormalMildly AbnormalNegativeCardiac CatheterizationExercise Imaging StudyReversible IschemiaNo Reversible IschemiaMedical Treatment
116 Recommendations for Hormone Replacement Therapy (HRT) After Acute MI Class IIa Recommendations1. HRT with estrogen and progestin for secondary prevention of coronary events should not be given de novo to postmenopausal women after AMI2. Postmenopausal women who are already taking HRT with estrogen plus progestin at the time of AMI can continue their therapyHERS Study: JAMA 1998;280:605-13
117 Initial Treatment A = Aspirin and Antianginal therapy B = Beta-blocker and Blood pressureC = Cigarette smoking and CholesterolD = Diet and DiabetesE = Education and Exercise
118 Algorithm for the Evaluation and Management of Patients Suspected of Having an ACS. Symptoms Suggestive of ACSNoncardiac DiagnosisChronic Stable AnginaPossible ACSDefinite ACSTreatment as indicated by alternative diagnosisSee ACC/AHA/ACP Guidelines for Chronic Stable AnginaNo ST elevationST elevationNondiagnostic ECG Normal Initial serum cardiac markersST and/or T wave changes Ongoing pain Positive cardiac markers Hemodynamic abnormalitiesNo recurrent pain;Negative follow-up studiesObserve Follow-up at 4-8 hours; ECG, cardiac markersStress 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 therapyRecurrent ischemic pain or positive follow-up studiesDiagnosis of ACS confirmedNegative: Potential diagnoses: nonischemic discomfort low-risk ACSPositive: Diagnosis of ACS confirmedSee ACC/AHA Guidelines for Acute MIArrangement for outpatientfollow-upAdmit to hospital Manage via acute ischemia pathway
119 III. Hospital Care A. Anti-ischemic Therapy B. Antiplatelet and Anticoagulation TherapyC. Risk StratificationD. Early Conservative vs. Invasive Strategies
120 Acute Ischemic Pathway Aspirin Beta-blockers NitratesAntithrombin regimenGP IIb/IIIa inhibitor Monitoring (rhythm and ischemia)Recurrent Ischemia and/or ST segment shift, or Deep T-wave Inversion,or Positive cardiac markersEarly Invasive strategyEarly Conservative strategyImmediate angiography12-24 hour angiographyRecurrent symptoms/ischemiaHeart failureSerious arrhythmiaPatient stabilizesEvaluate LV functionStress TestEF < .40EF .40Low riskNot low riskFollow 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 pain2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present4. 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 pain2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present4. 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 pain2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present4. 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 Therapyin 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 therapyElevated TnT or TnINew or presumed new ST-segment depression at presentationRecurrent 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 testingDepressed 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 CAD2. 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 testing5. 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 mellitus7. 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 ClassificationAgency for Health Care Policy Research
134 Unstable Angina pathogenesis Plaque disruptionPassive plaque disruption soft plaque with high concentration of cholesteryl esters and a thin fibrous capActive plaque disruption macrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture
135 Unstable Angina pathogenesis Acute ThrombosisVulnerable plaquedisrupted plaque with ulcerationoccurring in 2/3 of unstable patientsthe exposed lipid-rich core abundant in cholesteryl ester is highly thrombogenicSystemic Hypercoagulable Statedisrupted plaque with erosionoccurring in 1/3 of unstable patients
136 Unstable Angina pathogenesis Vasoconstrictionthe culprit lesion in response to deep arterial damage or plaque disruptionarea of dysfunctional endothelium near the culprit lesionplatelet-dependent and thrombin-dependent vasoconstriction, mediated by serotonin and thromboxane A2
137 Acute Coronary Syndrome Process of resolutionspontaneous thrombolysisvasoconstriction resolutionpresence of collateral circulationDelayed 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 painAssociated symptoms from the autonomic nervous systemnausea, vomiting, diaphoresisPersistent ST-segment depression after resolution of chest pain
139 Prinzmetal’s Angina clues to diagnosis Transient ST-segment elevation during chest painIntermittent chest painoften repetitiveusually at resttypically in the early morning hoursrapidly relieved by nitroglycerineSyncope (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 HeparinRESTORE TirofibanEPIC Abciximab0.4EPILOG AbciximabIMPACT II IntegrelinBolusBolus + InfusionLow doseHigh doseThe EXCITE Trial Investigators
143 Unstable Angina Anti-platelet Therapy SummaryThe 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 Heparinrecommendation is based on documented efficacy in many trials of moderate sizemeta-analyses (1,2) of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleedingtitrate PTT to 2x the upper limits of normal1. Circulation 1994;89:81-882. JAMA 1996;276:
145 Unstable Angina Anti-coagulant Therapy Low-molecular-weight heparin advantages over heparin:better bio-availabilityhigher ratio (3:1) of anti-Xa to anti-IIa activitylonger anti-Xa activity, avoid reboundinduces less platelet activationease of use (subcutaneous - qd or bid)no need for monitoring
146 Unstable Angina Anti-coagulant Therapy Low-molecular-weight heparinESSENCE 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 heparinN Eng J Med 1997;337:
147 MITI: Mortality, Infarct Size, and Time P=0.04P<0.001PercentLecture NotesThe 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 CohortP=0.001Mortality (%)Lecture NotesA 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 performedDoor-to-Balloon Time (minutes)Berger PB, et al. Circulation. 1999;100:14-20.
149 Patency and Mode of Reperfusion 90-minutepatencyLecture NotesBased on the open-artery hypothesis, reperfusion must be early, full, andsustained 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.EDarrivalDrugadministrationTime (minutes)Adapted from Gibson CM. Ann Intern Med. 1999;130:
150 ED Time Point 3: DECISION The Four DsTime of OnsetED Time Point 1: DOORED Time Point 2: DATAED Time Point 3: DECISIONED Time Point 4: DRUGTime Interval IIIDecision to drugTime Interval IIECG to decision to treatTime Interval IDoor to ECGLecture NotesIn 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 elevationAspirin, beta-blocker, antithrombin12 h>12 hEligible for fibrinolytic therapyFibrinolytictherapy contraindicatedNot a candidate for reperfusion therapyPersistent symptoms?therapyPrimary PTCA or CABGNoYesOther medical therapy: ACE inhibitors? NitratesConsider reperfusion therapyLecture NotesPrompt 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 mortalityAchievement of early, complete reperfusion may be more feasible with fibrinolytic therapy than with primary PTCAMaximal benefits of fibrinolytic therapy are attained within the first hour of symptom onset, although benefits extend out to 12 hoursContinued efforts are needed to minimize door-to-drug timeLecture NotesIn 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 OverviewEstimated ,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 decliningRemains principal cause of death in Western world
154 Acute MI Impact of Modern Critical Care on Mortality Defibrillation HemodynamicMonitoringb-BlockersAspirinThrombolysisPTCAAdapted from Antman, Braunwald In:Braunwald ed. Heart Disease p 1184.
155 Management of Acute MI Diagnosis Risk Stratification Acute Therapy ReperfusionAdjunctiveComplicationsPre-Discharge Management
156 Diagnosis of Acute MI History Classic symptoms: intense, oppressive chest pressure radiating to left armOther symptoms:chest heaviness, burningradiation to jaw, neck, shoulder, back, armsnausea, vomitingdiaphoresisdyspnealightheadednessSymptoms may be mild or subtle
157 Diagnosis of Acute MI Physical Examination Tachycardia or bradycardia ExtrasystolesS3 or S4, mitral regurgitation murmurLung ralesHypertension or hypotensionPallor, distress
158 Diagnosis of Acute MI Electrocardiogram Defines location, extent, and prognosis of infarctionST elevation diagnostic of coronary occlusionQ-waves do NOT signify completed infarctionST depression or T inversion: unlikely total coronary occlusionST elevation in RV4 for RV infarctionObserve up to 24 hrs for non-diagnostic ECGDifferentiate 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 abnormalitiesAbsence of contralateral wall hyperkinesia suggests multivessel disease or IRA recanalizationAssess LV function, prior infarctsMore sensitive than ECG for RV infarction
162 Diagnosis of Acute MI Coronary Angiography May be necessary for equivocal symptoms and ECGe.g. patients with prior CABG, previous MI, myocarditis with diffuse ECG D’s, non-characteristic D’s on ECGFinding of acutely-occluded vessel diagnosticAllows mechanical reperfusion
163 Acute MI Coronary Angiography Incorporated in primary, rescue PTCA strategiesIf ischemia, spontaneous or exercise-induced or complicated (CHF, arrhythmia)Controversial if uncomplicated MIDelineates anatomy but may potentiate unneeded revascularizationVery low risk but appreciable costKey prognostic indicator
164 Management of Acute MI Diagnosis Risk Stratification Acute Therapy ReperfusionAdjunctiveComplicationsPre-Discharge Management
165 Acute MI - Risk Stratification The GUSTO Pyramid - 30 Day Mortality ModelHXCV 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 OutcomeCategory Occlusion Site ECG 1-YearMortality1. Prox LAD before septal ST V1-6, I, aVL 25.6%fasicular or BBB2. 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, V5-64. Moderate-to- proximal RCA ST II, III, aVF and 8.4%large inferior or LCX V1, V3R, V4R or(post, lat, RV) V5-6 orR > S V1-25. Small inferior distal RCA or ST II, III, aVF only 6.7%LCX branch
167 Acute MI - Risk Stratification Ejection FractionMortality (2-Year)Gottlieb et al. Am J Cardiol 1992;69:
168 Acute MI - Risk Stratification Hemodynamic Subgroups - Killip ClassGISSI-1 (%)Killip Definition Incidence Control LyticClass Mortality MortalityI No CHFII S3 gallop orbasilar ralesIII Pulmonary edema(rales >1/2 up)IV Cardiogenic shock
169 Management of Acute MI Diagnosis Risk Stratification Acute Therapy ReperfusionAdjunctiveComplicationsPre-Discharge Management
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 statsome data suggest first dose should be 650 mg to achieve full antiplatelet effectContinue 325 mg per day indefinitely
173 Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83. T-PA and HeparinAngio 90 min 18 hrs 40 hrs 80 hrs 7 days+ASA +ASA +ASA +ASA +ASATopol 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 bleedingDiscontinue after 24 hrs, except for:atrial fibrillationrecurrent ischemiaanteroapical MI for CVA prophylaxis
175 Acute MI IV Heparin Optimal aPTT appears to be 50 to 70 seconds Not indicated with streptokinaseGISSI-2/Int’l and ISIS-3 SK+ASA=SK+ASA+SQ hepGUSTO-I SK+IV hep = SK+SQ hep Risk (at higher levels) of ICBGUSTO-II
176 Adjunctive Therapy for Acute MI Beta Blockers (Prior to Thrombolytic Era)Pooled Analysis - 7 Day Outcome> 29,000 Patients (26 Trials)p<0.02p<0.02p<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 blocker10% discontinued due to hypotension or bradycardiaTIMI Study Group. N Engl J Med 1989;320:618.
178 Beta Blockers in Acute MI Pooled Analysis of Randomized TrialsStudyAgentNMortality Odds Ratio & 95% CI12Control BetterRx BetterISIS-116,027AtenololDuringMIMIAMI5,778MetoprololTIMI IIB1,434MetoprololNorwegian1,884TimololPostMIBHAT3,837PropranololHennekens et al. NEJM 1996;335:1660.
179 Beta Blockers in Acute MI RecommendationsIV to oral beta blocker therapy in patients without contraindications in first 24 hoursAvoid early therapy in patients with bradycardia, hypotension, inferior MI, CHF, impaired LV function, AV block, asthmaContinue treatment for at least 2-3 years
180 Adjunctive Therapy for Acute MI ACE InhibitorsOutcome in “Megatrials”Total 85,064 PatientsMortality Reduction = 5 lives/1000 Rx’dp=0.57p=0.02p=0.0327,44227,3829435946056665679
181 ACE Inhibitors in Acute MI Pooled Analysis of Randomized TrialsStudyAgentNMortality Odds Ratio & 95% CI12ISIS-458,050CaptoprilDuringMIGISSI-319,394LisinoprilCONSEN II6,090EnalaprilatSAVE2,231CaptoprilPostMIAIRE2,006RamiprilTRACE1,749TrandolaprilRx BetterControl BetterHennekens et al. NEJM 1996;335:1660.
182 Adjunctive Therapy for Acute MI MagnesiumLIMIT-2ISIS-4p < 0.05p = NSWoods et al.Lancet 1992;339:1553.ISIS-4 Collab GroupLancet 1995;345:669.
183 Magnesium in Acute MI Summary Mortality benefit of empiric Rx - conflicting results of randomized trialspossibly due to late administration and low mortality in the ISIS-4 trialCorrect 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 AntagonistsAgentNOdds Ratio & 95% CICa+2AntControl15.0%Nifedipine13.0%135810.8%Verapamil13.3%177513.5%Diltiazem2466Verapamil/Diltiazem424112.4%13.4%13.0%Pooled13.3%559912Less MortalityMore MortalityHeld et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.52.
185 Management of Acute MI Diagnosis Risk Stratification Acute Therapy ReperfusionAdjunctiveComplicationsPre-Discharge Management
186 Complications of Acute MI Extension / IschemiaArrhythmiaPericarditisExpansion / AneurysmAcute MIRV InfarctHeart FailureMechanicalMural Thrombus
187 Management of Acute MI Intra-Aortic Balloon Pump Counterpulsation Decreases systemic afterloadIncreases diastolic aortic pressureReduces myocardial oxygen demandImproves systemic / end-organ perfusionVariable 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 VSDRefractory myocardial ischemiaRefractory ventricular arrhythmiasUseful 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 edemaVSD or papillary muscle ruptureCardiogenic shock or progressive hypotensionHypotension unresponsive to fluid RxNeed for inotropic or IABP supportRV infarctionRefractory VTTamponade
190 Acute MI - Recurrent Infarction / Ischemia PathophysiologyIn distribution of infarct vessel:IRA reperfusion, then reocclusionthrombus propogation, branch occlusiondistal embolizationreduced coronary perfusion pressure with severe residual IRA stenosisreduced collateral flow from stenosed arteryAt a distance:reduced collateral flow from IRAnew coronary thrombus (hypercoagulable state)reduced systemic perfusion pressureincreased myocardial oxygen consumption
191 Acute MI - Complications Recurrent Ischemia / InfarctionPrevention:AspirinBeta blockersACE inhibitors with low LVEF? heparin with fibrin-specific lytics (reocclusion)Treatment:Pharmacologic (beta blockers, nitrates)IABPUrgent revascularizationRepeat lytics (antibodies to SK)
192 Acute MI - CHF and Shock Pathophysiology Extensive (or multiple) LV infarction(s) - systolic dysfunctionImpaired relaxation, compliance due to infarction or ischemia - diastolic dysfunctionExtensive RV infarction or ischemiaVSD or acute severe MRTamponade (w/ or w/o free wall rupture)Otherse.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 ShockHemodynamic SubsetsSubset PCWP CI Clinical Setting(mm Hg) (l/min)1 < 18 > 2.2 asymptomatic2 > 18 > 2.2 pulmonary congestion3 < 18 < 2.2 RV failure,hypovolemia, orprofound venodilation4 > 18 < 2.2 severe LV dysfxncardiogenic shockForrester JS et al. NEJM 1976;295:1356 and 1404.
194 Acute MI - Cardiogenic Shock Outcome with PTCAPooled Analysis of 22 Retrospective StudiesHistorical control mortality ~ 80%Total 646 ptsPTCA success rate = 76%Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 461.
195 Acute MI - Mechanical Complications Free Wall RuptureLess frequent (1-3.4%), but earlier, with thrombolysisUncontained sudden EMD or asystolePseudoaneurysm transient hypotension, EMD, bradycardia, repetitive emesis, restlessnessEchocardiogram usually diagnosticSurgical repair - may require pericardiocentesis for uncontained rupture
196 Acute MI - Mechanical Complications Interventricular Septal RuptureIncidence 1-3% of transmural MIsAcute shock, pulmonary edema, right heart failure, new loud pan-systolic murmur (thrill in 50%)Diagnose with echocardiogram or O2 saturation step-upMedical stabilization and IABP for CHF, shockEarly 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
198 Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445. Acute MIThe “Late Open Artery”n Time to Follow-Up Patent OccludedAngio IRA IRA(days) (months) Mortality MortalityCigarroa % 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 RegurgitationTransient MR common in early MI (20-40%)Associated with advanced age, prior MI, infarct extension, recurrent chest pain, CHF, female genderPersistent MR, even mild, associated with increased long-term mortality post-MIMay be due to papillary muscle or chordal rupture or to geometric changes (dilation) of ventricle and annulusMost common with inferior MI (single blood supply to posteromedial papillary muscle) - MI often small
200 Acute Mitral Regurgitation Diagnosis and Managementharsh, short systolic murmur - may be muffledsudden CHF +/- hypotension or shock 2-7 days post MIechocardiography (surface or TEE) usually diagnostic - mobile papillary muscle head or flail MV leafletLV function often normal or hyperkineticsudden hemodynamic deterioration commonstabilize medically, IABP, then surgical repairsurgical mortality high if shock is presentrole of surgery in MR not due to rupture less clear
201 Acute MI - Complications Right Ventricular InfarctionAssociated with occlusion of proximal RCAClassic triad by hypotension, JVP, clear lungs specific but insensitiveKussmaul’s sign, JVP > 8 cm H2O sensitive and specificEKG: ST in RV4Echo: RV dilation and hypokinesiaPA catheter: RA >10 mm, RA/PCWP ratio > 0.8
202 Acute MI - RV Infarction ManagementExtensive irreversible infarction is unusual - transient ischemic dysfunction with long-term recovery commonMarked by sensitivity to preload reduction (nitrates, diuretics, morphine), bradycardia, AV blockFluid volume infusion for hypotension and low cardiac outputPCWP elevation may occur due to septal shiftDobutamine if fluids RA and PCWP without improved BP and CI
203 Prophylactic Lidocaine Acute MI - ArrhythmiasProphylactic LidocaineProphylactic use for suppression of VT or VF controversialOverview of randomized trials:33% reduction in primary ventricular arrhythmiastrend 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 TrialsStudyAgentNMortality Odds Ratio & 95% CI0.1110CAST1,498Enc / FlecClassICAST II1,325MoricizineEMIAT1,486AmiodaroneCAMIAT1,202AmiodaroneClassIIISWORD3,121d-SotalolJulian et al1,456l-SotalolRx BetterControl BetterNEJM 1996;335:1660. Lancet 1997;349:667 and 675.
205 Ventricular Tachycardia or Fibrillation Acute MI - ArrhythmiasVentricular Tachycardia or FibrillationPrognosis of VT or VF in first 48 hours controversialMILIS - no increased in-hospital mortalityGISSI - increased in-hospital mortalityNo increased mortality after hospital dischargeVT or VF after first 48 hours associated with poorer long-term prognosisAcute management - K+ replacement, antiarrhythmic therapy (lidocaine, procainamide, or amiodarone) if stable, electrical shock if unstableLong 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 yearRate control with digoxin, or (without CHF) beta blockers, verapamil, or diltiazemConsider IV amiodaroneElectrical cardioversion for hemodynamic compromise or ischemia
207 Indications for Temporary Pacing Acute MI - ArrhythmiasIndications for Temporary Pacingasystolecomplete (third-degree) AV blocksecond-degree Mobitz II AV blocksecond-degree Mobitz I AV block with hypotensionnew bifascicular block, esp with first-degree AV blocksymptomatic bradycardia, unresponsive to atropineTranscutaneous standby pacing for new LBBB, sick sinus syndrome with sinus pauses
208 Indications for Permanent Pacing Acute MI - ArrhythmiasIndications for Permanent Pacingpersistent complete (third-degree) AV blockpersistent sinus node dysfunction - symptomatic bradycardiaintermittent second-degree Mobitz II or third-degree AV blocksecond-degree Mobitz II or third-degree AV block with new bundle branch block
209 Management of Acute MI Diagnosis Risk Stratification Acute Therapy ReperfusionAdjunctiveComplicationsPre-Discharge Management
210 Pre-Discharge Management Acute MIPre-Discharge ManagementRisk stratificationCatheterization and revascularization strategyElectrophysiologic evaluation for VT or VFLifestyle modification: diet, exercise, tobaccoPharmacologic therapy
211 Acute MI - Risk Stratification Post-MI Revascularization StrategyLow RiskHigh Risk*Nl LVSF LVSFNl LVSF LVSFStress ImagingorCatheterizationStress ImagingDirectCathNormalAngiographyRevascularization* (Re) MI or CP, VT, CHF, Prior MI, Prior Revascularization
212 Pharmacologic Therapy on Hospital Discharge Acute MI ManagementPharmacologic Therapy on Hospital DischargeAspirin indefinitely (ticlopidine or clopidogrel for aspirin allergy or intolerance)Beta blockers for at least 2-3 yearsACE inhibitors for CHF, LVEF<40%, or large infarction (even with preserved LVEF)Lipid lowering agentsCoumadin for mural thrombus, extensive anterior infarct, DVT, atrial fibrillation
213 Thrombolysis in Acute MI Relative ContraindicationsUncontrolled HTN (BP > 180/110) on presentationHistory prior CVA beyond 1 yrAnticoagulant Rx with INR > 2-3; bleeding diathesisRecent trauma (within 2-4 wks)Noncompressible vascular puncturesRecent internal bleeding (within 2-4 wks)PregnancyActive peptic ulcerPrior exposure (5 day - 2 yr) for SK or APSAC
214 Thrombolysis in Acute MI Absolute ContraindicationsPrevious hemorrhagic strokeCVA within previous yrIntracranial neoplasia or AVMActive internal bleeding (not menses)Suspected aortic dissection
215 Myocardial Reperfusion The Original ParadigmRe-establishInfarct VesselPatencyLimit InfarctSize Mortality
216 Days from Randomization GUSTOMortality TrialAngiographic Trial41,021 Patients30-day Outcome2,431 PatientsTIMI 3 flowSK(IV)SubQt-PA +Accel.t-PA86421012141618202224262830% MortalityDays from Randomization
220 Thrombolysis for Acute MI Electrocardiographic Criteria for TherapyPooled Analysis of Randomized TrialsEKGOdds Ratio & 95% CI0.3313Placebo BetterLysis BetterPlaceboLysis23.6%BBB18.7%16.9%ST Anterior13.2%8.4%ST Inferior7.5%13.4%ST Other10.6%13.8%ST15.2%5.8%Other Abnorm5.2%2.3%Normal3.0%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 TrialsTrialPTCALysisN2.0%Zijlstra7.4%389Odds Ratio & 95% CI0.1110Lysis BetterPTCA BetterSKTrials9.3%Grinfeld10.3%1126.5%DeWood4.5%902.6%PAMI3954.3%Gibbons3.6%1030.0%Ribichini2.4%833.2%Elizaga10.6%1895.7%GUSTO II7.0%11384.4%Pooled25996.0%Ribeiro100t-PAAccelPooled 32% RRTopol, Van de Werf. Textbook Cardiovasc Med 1998;p416
224 Acute MI: 1995RESCUE156 pts < 8 hours chest pain, ant. MI with occluded LAD PTCA successful in 92% of patientsOutcomes at 30 Days
225 Pathophysiology of Combination Therapy in AMI Reduces Reinfarction* Thrombus % Stenosis Minimum Diameter Myocardial Blush ST ResolutionThere 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.ReferencesGibson 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 FlowFacilitates PCI Myocardial Flow*Gibson et al. J Am Coll Cardiol. 1995;25:Gibson et al. Circulation. 2001;103:
226 Recent Clinical Trials GP IIb/IIIaReceptor InhibitorTrialLyticAnticoagulantGUSTO-V100% r-PA50% r-PANoneAbciximabStandard-dose heparinLow-dose heparinASSENT-3100% TNK-tPA50% TNK-tPANoneAbciximabACC/AHA heparin doseLow-dose heparinEnoxaparinSeveral 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.ReferencesThe 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:ENTIRE50% TNK-tPA100% TNK-tPAAbciximabNoneUnfractionated heparinEnoxaparin
227 Clinical Trials: Ongoing GP IIb/IIIaReceptor InhibitorTrialLyticAnticoagulantFASTER50% TNK-tPA75% TNK-tPA100% TNK-tPATirofibanLow-dose heparinINTEGRITI50% TNK-tPA75% TNK-tPA100% TNK-tPAEptifibatideLow-dose heparinShown 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 6054%50t-PA6.3%4032%% TIMI Grade 3 Flow30Recently 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.ReferencesThe 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;329:20SK7.4%10t-PASK5678The 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 Trials100Lytic aloneCombination8078737370646056565454% Patients With TIMI Grade 3 Flow474040While 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%.ReferencesThe 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;101:2029263588788981008175329321GUSTO-I90 minT14 t-PA90 minT14 r-PA90 minSPEED60-90 minINTRO-AMI60 minPooled60-90 min
230 SPEED: Results of Dose-Confirmation Phase 100TIMI-2There was a 7.4% improvement in the rate of TIMI Grade 3 flowIf 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-38028.721.660Patency (%)54.947.540The 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.ReferencesThe 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;329:20n=109n=115r-PA Ur-PA 5+5 U + AbxThe SPEED Study Group. Circulation. 2000;101:
231 GUSTO-V: Study Design ST , lytic eligible, < 6 h (n=16,588) ASANo AbciximabAbciximab2 x 10 U bolus (30’)Full-dose r-PA2 x 5 U bolus (30’)Half-dose r-PAStandard Heparin:5000 U bolus followed by 800 U/h (< 80 kg) or U/h ( 80 kg) infusionLow-dose Heparin:60 U/kg bolus followed by 7 U/kg/h infusionThe 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 randomizationECG evidence of AMI with ST-segment elevation or new left-bundle branch blockExclusion criteria included the following:One blood pressure measurement higher than 180 mmHg systolic and 110 mmHg diastolicWeight >120 kgReferencesThe 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 days2º end point: clinical and safety events at 30 daysThe GUSTO-V Investigators. Lancet. 2001;357:
232 Primary End Point: 30-Day Mortality 65.9%5.6%4P=.43 for superiority% MortalityNon-Inferiority RR 0.95(95% CI, )2The 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).ReferencesThe 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)51015202530DaysThe GUSTO-V Investigators. Lancet. 2001;357:
233 GUSTO-V: Noninferiority Analysis Upper Boundary of 95% CI for Noninferiority1.11OR and 95% CINon-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.ReferencesThe 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;357:0.0Abciximab + Half-dose r-PA superior1.0Full-dose r-PA superior2.0Adapted 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 85048%1.07.4%0.91%0.97400.865.9%37%0.750.59%300.640.5200.430.32Prior 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.ReferencesThe 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;357:100.210.110,1388,26010,1388,26010,1388,260GUSTO IIIGUSTO VGUSTO IIIGUSTO VGUSTO IIIGUSTO VDeathAnterior MIICHThe GUSTO-III Investigators. N Engl J Med. 1997;337:The GUSTO-V Investigators. Lancet. 2001;357:
235 GUSTO-V: Causes of Reinfarction 4P<.00013.5r-PA3r-PA + Abx2.72.3Myocardial Infarction (%)184.108.40.206The 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.ReferencesThe 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;357:10.50.2AnyQ-waveEnzymaticIschemic STChange**Unblinded, unadjudicatedThe GUSTO-V Investigators. Lancet. 2001;357:
236 Non-Intracranial Bleeding Through Discharge/Day 7 3025r-PA24.6r-PA + Abx20.020% of Patients1513.711.410Combination 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).ReferencesThe 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;357:5.7103.54.01.81.10.5SevereBleedingModerateBleedingMildBleedingAnyBleedingReceivingTransfusionsThe 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) 2.12P=.531.5% of Patients1.21.11In 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.ReferencesThe 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=.6220.127.116.11.324/623021/619325/203031/213537/717228/717912/108824/1149 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*25.42520UrgentPCI (%)15Through 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.ReferencesThe 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;357:108.6*5.65r-PAr-PA + Abx*P<.0001.The GUSTO-V Investigators. Lancet. 2001;357:
239 GUSTO-V: Event Rates in Those Requiring Urgent PCI 12r-PAn=1173r-PA + Abx109.69.086.7Myocardial Infarction (%)65.44.84Although 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.ReferencesThe 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;357:2.82DeathRepeat MIDeath Plus Repeat MIHeartwire News. September 2, GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?
240 GUSTO-V: ConclusionsCompared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted inA mortality rate that was not inferior to r-PA monotherapyFewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation)A lower rate of urgent revascularizationMore noncerebral bleeding complications, transfusions, and thrombocytopeniaA higher rate of ICH in elderly patients over the age of 75 yearsCompared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in:A mortality rate that was not inferior to r-PA monotherapyFewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation)A lower rate of urgent revascularizationMore noncerebral bleeding complications, transfusions, and thrombocytopeniaA higher rate of ICH in elderly patients over the age of 75 yearsReferencesThe 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 enoxaparinFavorable effects of LMWHs in recent small-scale thrombolysis trialsHigher late patency: HART-2 ASSENT-Plus AMI-SKLess reocclusion: HART-2Fewer reinfarctions: ASSENT-Plus AMI-SK Wilson, et al.ASSENT-3 is the first large-scale trial to test LMWHShown 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)RandomizedThe 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 daysHalf-dose TNK-tPA plus the platelet GP IIb/IIIa receptor inhibitor, abciximab, for 12 h and low-dose UFHFull-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 randomizationECG evidence of AMI with ST-segment elevationExclusion 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.ReferencesThe 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 EnoxaparinHalf-dose TNK-tPA Plus Abciximab Plus Low-dose HeparinFull-dose TNK-tPA Plus Weight- adjusted UFHThe 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).ReferencesThe 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=.000120P=.0009*P=.0002*15.41511.411.1% Risk of 30-Day D/MI/Ref Isch10Shown 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).ReferencesThe 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;358:5TNK-tPA + EnoxTNK-tPA + AbxTNK-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 ICH3-way P=.006220P=.0146*P=.0057*17.01514.213.8% Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH10Shown 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).ReferencesThe 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;358:5TNK-tPA + EnoxTNK-tPA + AbxTNK-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 Point20201818UFHUFH1616Abx1414Enox*1212Enox*Abx*Probability (%)10Probability (%)108866Shown 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.ReferencesThe 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;358:44log-rank P=.0001*vs UFHlog-rank P=.0062*vs UFH + Abx225101520253051015202530Days to death, reinfarction, or refractory ischemiaDays to death, reinfarction, refractory ischemia, ICH, or major bleedingReprinted 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 Age45P=.001*4036.9353028.025.525% Risk of 30-Day Efficacy and Safety End Point2015This 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).ReferencesThe 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;358:105TNK-tPA + EnoxTNK-tPA + AbxTNK-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 Diabetes30P=.007*2522.32016.5% Risk of 30-Day Efficacy and Safety End Point1513.910This 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).ReferencesThe 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;358:5TNK-tPA + EnoxTNK-tPA + AbxTNK-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 103-way P=.2586.66.065.4% Risk of 30-Day Mortality4The 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.ReferencesThe 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;358:2TNK-tPA + EnoxTNK-tPA + AbxTNK-tPA + UFH
250 ASSENT-3: 30-Day Death or MI 103-way P=.01918.104.22.168% Risk of 30-Day Death or MI4The enoxaparin arm was associated with the lowest rate of death or MI at 30 days (3-way P=.0198).ReferencesThe 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;358:2TNK-tPA + EnoxTNK-tPA + AbxTNK-tPA + UFH
251 ASSENT-3: In-Hospital Recurrent MI 53-way P=.00094.2432.7% Risk of In-Hospital Recurrent MI2.22The enoxaparin and abciximab arms were associated with a lower rate of recurrent MI compared with the UFH arm.ReferencesThe 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;358:1TNK-tPA + EnoxTNK-tPA + AbxTNK-tPA + UFH
252 ASSENT-3: In-Hospital Refractory Ischemia 103-way P<.000186.56% Risk of 30-Day Refractory Ischemia4.64The enoxaparin and abciximab arms were associated with a lower rate of refractory ischemia compared with the UFH arm.ReferencesThe 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;358:3.22TNK-tPA + EnoxTNK-tPA + AbxTNK-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-wayAny thrombocytopenia <.0001Thrombocytopenia <.0001<20,000 cells/µL20,000 to 50,000 cells/µL50,000 to <100,000 cells/µLBleeding episodesTotal 25.6* <.0001Major 3.0*Minor 22.6* <.0001Blood 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.ReferencesThe 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 UnclassifiedHemorrhagic conversionIschemic stroke*Intracranial hemorrhageTotal strokes0.150.070.400.640.940.881.491.62Abx (n=2017)Enox (n=2040)0.590.050.770.000.570.540.980.931.52P-ValueUFH (n=2038)Total stroke and intracranial hemorrhage rates were similar in the three groups.ReferencesThe 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 8ASSENT-3: In-Hospital PCIGUSTO-V: Urgent PCI76.765.45Mortality (%)43.73One 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.ReferencesThe 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;358:2.72.521TNK-tPA + EnoxTNK-tPA + AbxTNK-tPA + UFHr-PA + UFHr-PA + Abx
256 How Does Actual Weight Compare to Estimated Weight? Correlation Between Estimated and Actual Patient Weight in TIMI 10B188.5R2=0.93, P<.0001Actual 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.ReferencesCannon 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.40.536.4181Estimated 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.ReferencesCannon 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.ReferencesThe 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 NotesWith 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.”ReferencesThe 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)ASAStandard 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 hENOX 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 IssuesShould 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: FiltersSmall embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitorsVasoconstrictor release: GP IIb/IIIa inhibitorsSpasm: Adenosine, Ca channel blockers, alpha blockers, avoid over sizing with PCI, high pressure inflations, serotonin inhibitors, endothelin inhibitorsEndothelial & Myocardial swelling: Myocardial cooling, Ca channel blockers, DHEA, Na / H pump inhibitors, anti-inflammatory approachesThe 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 inhibitorsPatients with acute MI may benefit from GP IIb/IIIa inhibition + thrombolysisASA 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 & LMWHAntithrombin therapy treats acute exacerbation via short-term treatmentUFH+ASA better than placebo or ASA alone in reducing CVD/MI/RALMWH has clinical advantages over UFH, and is a useful agent early in treatmentSince 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+ patientsNeutralizes clot-bound and soluble fibrin; no allergic reactions (lack of HIT)In acute MI, hirudin and UFH have equivalent effects as adjunctive therapy to thrombolysisIn PTCA, hirudin is associated with fewer cardiac events compared to UFHIn 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 ACSHirudin appears to be a safe, superior alternative to UFHLonger treatment durations need to be assessed for possible long-term benefitsCombining a thrombin-specific inhibitor (eg, hirudin) with a GP IIb/IIIa blocker may be an even more effective antithrombotic therapy for ACSComparisons 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 CADAdvantages of Stress Echocardiography1. Higher specificity2. Versatility - more extensive evaluation of cardiac anatomy and function3. Greater convenience / efficacy / availability4. Lower costAdvantages of Stress Perfusion Imaging1. Higher technical success rate2. Higher sensitivity - especially for single vessel coronary disease involving the left circumflex3. Better accuracy in evaluating possible ischemia when multiple resting LV wall motion abnormalities are present4. 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 Protocolminus 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 womenN Engl J Med 1991;325:849-53
269 Survival According to Risk Groups Based on Duke Treadmill Score 4 -Year AnnualRisk Group (Score) Total Survival MortalityLow ( +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 outcomeproximal coronary stenosessevere left main coronary artery stenosisCASS registry of medically treated patients, the 12-year survival rateCoronary arteries Ejection fractionnormal 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 therapyMale genderHypertensionDiabetes mellitusHypercholesterolemia/HypertriglyceridemiaSmokingFamily history of early CADfemale age < 65; male age < 55Past personal history of PVD or CVA
272 Risk Factors for Coronary Artery Disease (con’t) Left ventricular HypertrophyCocaine/Ethanol AbuseObesitySedentary LifestyleOral contraceptivesHomocysteine elevationFibrinogen, C-reactive protein, Lp (a)
273 Guidelines to Reduce Risk For Patients With Coronary Disease and other vascular disease Cessation of smokingLipid Management GoalsPrimary Goal: LDL < 100 mg/dlSecondary: HDL > 35 mg/dl TG < 150 mg/dlPhysical activity: 30 minutes 3-4 times per weekWeight managementAntiplatelet/anticoagulants:ASA 80 to 325 mg/day(or clopidogrel 75m/day)ACE inhibitors (post-MI for LVD)Beta blockers for high-risk patients post-MIBlood pressure control: goal < 130/85 mm HgAdapted from Smith, Circulation 1995;92:3
274 Medical Therapy For Patients with CAD or Other Vascular Disease Risk ReductionASA %Beta Blockers %ACE inhibitors %Statins %The four medications every atherosclerosis patient should be treated with, unless contraindications exist and are documentedAdapted from the UCLA CHAMP Guidelines 1994
275 TIMI IIIA Protocol Design 391 Patients with Unstable Angina / NQWMI IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockersAngio Exclusion:no CAD or LMainBaseline AngioRandomizePlacebot-PA0.8 mg/kg over 90 minsTIMI 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 weeksAngio hrsFollow-up 6 weeksCirculation 1993;87:38-52777
276 TIMI IIIA Primary Results Effects of tPA on Coronary Lesions BASELINE ANGIORAPHY:Apparent thrombusNo thrombus35%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 thrombus30%ANGIORAPHY AFTER tPA:Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NSTIMI 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++ blockersRandomizeEarly Conservative:ST Holter, ETT ThalliumCath/PTCA if +ischemiaEarly Invasive:Cath hPTCA/CABG prn2x2 Factorial:t-PA vs. PlaceboIn 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 weeksETT 6 weeks1o Endpoint t-PA:Death, MI, Rec Isch,+ ETT, Thalliumor ST HolterCirculation 1994;89:Follow-up 1 year777
278 TIMI IIIB Investigators. Circulation 1994;89:1545-56 Primary ResultstPA vs. Placebo in Non-ST Elevation ACSComposite EndpointDeath or MIICH% of PatientsHere 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 = NSP = 0.05P = 0.05TIMI IIIB Investigators. Circulation 1994;89:
279 TIMI IIIB Investigators. Circulation 1994;89:1545-56 Primary ResultsEarly Invasive vs. Conservative StrategyEvents at 42d Invasive Conservative p valueNo. PtsDeath (%) NSMI (%) NSD/MI/+ETT (%) NSRehosp Angina (%) <0.001D/MI/Rehosp (%)LOS (days) <0.001# Days rehosp <0.001In 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 MIExclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedurePatients 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 indicatorST deviation >0.1 mV_LBBBTw changeNo ECG changes2522.9Death or MI201511% of Patients22.214.171.124Among 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.126.96.36.199188.8.131.52.8In-Hospital6 Weeks1 YearStone 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 hrsEnrolled 6-24 hrsEnrolled 0-24 hrsP<0.001P <0.05P<0.0011404 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 <0.05Antman et al. NEJM 1996; 335:1342-9