dr. r.v.s.n.sarma, m.d., m.sc (canada) consultant physician and chest specialist 1, jayanagar,...

[email protected]@works

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

Consultant Physician and Chest Specialist

1, Jayanagar, Tiruvallur, Chennai -602 001

(04116) – 260593, 263665

Mobile 098940 60593

[email protected]

Ischemic Heart DiseaseIschemic Heart DiseaseIschemic Heart DiseaseIschemic Heart Disease

Diagnosis & Management Diagnosis & Management Diagnosis & Management Diagnosis & Management

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

“ There’s too much confusion,

Never, I can’t get neither no relief ”

Jimi Hendrix,

Purple Haze, 1968

“In this world, nothing can be said to be certain except death and taxes.”

Benjamin Franklin13 November 1789 (letter)

Lysis or Life-flight ?Lysis or Life-flight ?Lysis or Life-flight ?Lysis or Life-flight ?

Comorbidity of Atherosclerotic Disease Comorbidity of Atherosclerotic Disease a major health burdena major health burdenComorbidity of Atherosclerotic Disease Comorbidity of Atherosclerotic Disease a major health burdena major health burden

• Atherothrombosis

• major complications of atherosclerosis are thrombosis, with local occlusion or distal embolization

PADPAD

CADCAD CVACVA

Aronow WS, Ahn C. Am J Cardiol. 1994;74:64–65.

Atherosclerosis Time-lineAtherosclerosis Time-lineAtherosclerosis Time-lineAtherosclerosis Time-lineFoamFoamCells Cells

FattyFattyStreak Streak

IntermediateIntermediateLesion Lesion AtheromaAtheroma

FibrousFibrousPlaquePlaque

ComplicatedComplicatedLesion/Lesion/RuptureRupture

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

From FirstDecade

From ThirdDecade

From FourthDecade

Endothelial DysfunctionEndothelial Dysfunction

Left Coronary ArteryLeft Coronary ArteryLeft Coronary ArteryLeft Coronary Artery

Right Coronary ArteryRight Coronary ArteryRight Coronary ArteryRight Coronary Artery


Overview of CAD Presentation

• Assessment of CAD likelihood • Risk stratification based on findings• Anti-ischemic drug therapy• Anti-platelet/ anti thrombotic therapy• Invasive versus conservative strategy

– Primary PTCA versus Thrombolytic Rx.

• Secondary prevention and risk factor modification


Clinical AssessmentThe two critical questions

1. What is the likelihood that the signs and symptoms represent ACS secondary to obstructive CAD ?

2. 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)


History - Likelihood of ischemia

The 5 most important factors, ranked in the order

of importance, are

1. Nature of the anginal symptoms

2. Prior history of CAD

3. Sex

4. Age

5. Number of traditional risk factors present


Classical Angina

Angina is characterized as a deep, poorly localized

chest or arm discomfort that is reproducibly

associated with physical exertion or emotional stress

and is relieved promptly (in less than 5 min) with

rest and/or the use of sublingual nitroglycerin (NTG)


Clinical Classification of Chest Pain

Typical angina (definite) 1) substernal chest discomfort with a characteristic

quality and duration that is ... 2) provoked by exertion or emotional stress and 3) relieved by rest or nitroglycerin

Atypical angina (probable)meets 2 of the of characteristics

Noncardiac chest painmeets 1 of the typical angina characteristics

J Am Coll Cardiol. 1983;1:574, Letter


Differential Diagnosis of Prolonged Chest Pain

• AMI

• Aortic dissection

• Pericarditis

• Atypical angina pain associate with hypertrophic cardiomyopathy

• Esophageal, other upper gastrointestinal, or biliary tract disease

• Pulmonary disease– pneumothorax

– embolus with or without infarction

– pleurisy: infectious, malignant, or immune disease-related

• Hyperventilation syndrome

• Chest wall– skeletal

– neuropathic

• Psychogenic


Chest Pain ChecklistYES

� Ongoing chest discomfort ( 20 min and < 12 hours)

� Oriented, can cooperate

� Age > 35 y (> 40 if female)

� ECG done

� High-risk profile *

� Heart rate 100 bpm

� Blood pressure 100 mm Hg

� Pulmonary edema (rales > 1/2 way up)

� Shock

NO

� History of stroke or TIA

� Known bleeding disorder

� Active internal bleeding in past two weeks

� Surgery or trauma in past two weeks

� Terminal illness

� Jaundice, hepatitis, kidney failure

� Use of anticoagulants

• Systolic/diastolic blood pressure Right arm ____/____ Left arm ____/____

• 1. Pain began ____ AM/PM2. Arrival time ____ AM/PM3. Begin transport ____ AM/PM4. Hospital arrival ____ AM/PM

Check each finding. If all [YES] boxes are checked and ECG indicates ST elevation or new BBB, reperfusion therapy with fibrinolysis or primary PTCA may be indicated. Fibrinolysis is generally not indicated unless all [NO] boxes are checked and BP 180/110 mm Hg.

* Transport to a facility capable of angiography and revascularization if needed

Adapted from the Seattle/King County EMS Medical Record


Acute Coronary Syndrome

Ischemic DiscomfortUnstable Symptoms

No ST-segmentelevation

ST-segmentelevation

Unstable NSTEMI STEMI Angina (Non-Q MI) (Q-wave MI)

ECG(10 min)

Cardiac Biomarkers

HistoryPhysical Exam

(positive cardiac biomarker)


II IIaIIa IIbIIb IIIIII

ACC/AHA Classifications Expert Opinion and Recommendations

Intervention is useful and effective

Evidence conflicts/opinions differ but leans towards efficacy

Evidence conflicts/opinions differ but leans against efficacy

Intervention is not useful/effective and may be harmful

Intervention is useful and effective

Evidence conflicts/opinions differ but leans towards efficacy

Evidence conflicts/opinions differ but leans against efficacy

Intervention is not useful/effective and may be harmful

JACC 1999; Vol 33, No 7:2092-197


12 Lead Resting ECG

• should be recorded in all patients with symptoms suggestive of angina pectoris

• normal in 50% of patients

• a normal ECG does not exclude severe CAD; however, it does imply normal LV function with favorable prognosis


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

[email protected]@works Am J Cardiol 1982;49:1604-14

Risk Stratification: abnormal rest ECG• Evidence of >1 prior MI (Q waves or R wave in lead V1 for posterior

infarction)

• A "QRS score" to indicate the extent of old or new MI

• persistent ST-T wave inversions, particularly in leads V1 to V3 of the rest ECG, is associated with an increased likelihood of future acute coronary events and a poor prognosis

• LV hypertrophy by ECG criteria in a patient with angina pectoris is also associated with increased morbidity and mortality

• A decreased prognosis is also likely when the ECG shows left bundle-branch block, bifascicular block (often left anterior fascicular block plus right bundle-branch block), second- or third-degree atrioventricular block, atrial fibrillation or ventricular tachyarrhythmias


Risk stratification: Chest X-Ray

• often normal in patient with stable angina pectoris

• usefulness as a routine test is not well established

• findings associated with poorer long-term prognosis – cardiomegaly

– LV aneurysm

– pulmonary venous congestion

– left atrial enlargement

– calcium in the coronary arteries


Cardiac Troponins

• Advantages– powerful tool for risk stratification

– greater sensitivity and specificity than CK-MB

– detection of recent MI up to 2 weeks after onset

• Disadvantages– low sensitivity in very early phase of MI (< 6 h after symptom

onset)

– limited ability to detect late minor reinfarction

• Clinical recommendations– useful as a single test to efficiently diagnose NSTEMI (including

minor myocardial damage), with serial measurements


CK-MB

• Advantages– rapid, cost-efficient, accurate assays– ability to detect early reinfarction

• Disadvantages– loss of specificity in setting of skeletal muscle disease or injury,

including surgery– low sensitivity during very early MI (< 6 h after symptom onset)

or later after symptom onset (> 36 h) and for minor myocardial damage (detectable by troponins)

• Clinical recommendations– prior standard and still acceptable diagnostic test in most clinical

circumstances


Myoglobin

• Advantages– high sensitivity– useful in early detection of MI– detection of reperfusion– most useful in ruling out MI

• Disadvantages– very low specificity in setting of skeletal muscle injury or disease– rapid return to normal range limits sensitivity for later

presentations

• Clinical recommendations– should not be used as only diagnostic marker because of lack of

cardiac specificity


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.


Serum Cardiac Markers

• CK-MB subfomes for Dx within 6 hrs of MI onset• cTnI and cTnT efficient for late Dx of MI• CK-MB subform plus cardiac-specific troponin

best combination• Do not rely solely on troponins because they

remain elevated for 7-14 days and compromise ability to diagnose recurrent infarction


Myocardial Markers

MARKER 1st SEEN(median)

REL. (x Nl)

DURATION(hrs)

SENS.MI

SENS.U.A.

MYOGLOBIN 2-3 hr 12 18-24 85-90 ?

TROPONIN I 4-6 50 > 144 100 30

TROPONIN T 3-4 50 > 240 100 40

MB MASS 4-6 12 24-36 100 25

CK TOTAL 6-8 8 36-48 80-85 ?

CK ISOFORM 2-3 N/A 6-12 100 10?


10

Siz

e of

Myo

card

ial

Infa

rctio

n (g

ram

s)

0.01

100

0.001

1

0.1

ECHO CK,AST

CK-MB

TROPONINEKG


Enzymatic Criteria for Diagnosis of Myocardial Infarction

• Serial increase, then decrease of plasma CK-MB, with a change > 25% between any two values

• CK-MB > 10-13 U/L or > 5% total CK activity

• increasing MB-CK activity > 50% between any two samples, separated by at least 4 hrs

• if only a single sample available, CK-MB elevation > twofold

• beyond 72 hrs, an elevation of troponin T or I or LDH-1 > LDH-2


The Progressive Development of Cardiovascular Disease

Endstage Heart DiseaseEndstage Heart Disease

Congestive Heart FailureCongestive Heart Failure

Ventricular DilationVentricular Dilation

RemodelingRemodeling

Arrhythmia & Loss of MuscleArrhythmia & Loss of Muscle

Myocardial InfarctionMyocardial Infarction

Myocardial IschemiaMyocardial Ischemia

CADCAD

AtherosclerosisAtherosclerosis

Endothelial DysfunctionEndothelial Dysfunction

Risk FactorsRisk Factors

Coronary ThrombosisCoronary Thrombosis


Atherosclerosis: the Pathologic Process

OcclusionOcclusion

Acute EventAcute Event

EmbolismEmbolism

ChronicChronic Ischemia Ischemia

AtheroscleroticAtheroscleroticPlaquePlaque

PlaquePlaqueFissure/Fissure/

Cracking/Cracking/RuptureRupture

ThrombusThrombusIncorporatedIncorporated

intointo Atheroma Atheroma

ThrombusThrombusFormationFormation

StabilizedStabilizedPlaquePlaque


0 6 12 18 24 2 3 4 5 6 7 8 9 10

RE

LATI

VE

CO

NC

EN

TRAT

ION

DaysHours

TIME AFTER INFARCT

Normal

TroponinMyoglobin

CK, ASTLDH

Cardiac Enzyme bio-markersCardiac Enzyme bio-markersCardiac Enzyme bio-markersCardiac Enzyme bio-markers


MYOFIBER STRUCTUREMYOFIBER STRUCTUREMYOFIBER STRUCTUREMYOFIBER STRUCTURE

TnI

ActinTropomyosin

TnC TnT


Inferior MI changes fully evolvedInferior MI changes fully evolvedInferior MI changes fully evolvedInferior MI changes fully evolved


Posterior MI Posterior MI Posterior MI Posterior MI


ST ↓ - Ischemia Lateral wallST ↓ - Ischemia Lateral wall ST ↓ - Ischemia Lateral wallST ↓ - Ischemia Lateral wall


ST segment ST segment ↑↑– Acute evolving MI– Acute evolving MIST segment ST segment ↑↑– Acute evolving MI– Acute evolving MI


ST segment ST segment ↑↑– Inferio-lateral MI– Inferio-lateral MIST segment ST segment ↑↑– Inferio-lateral MI– Inferio-lateral MI


Evolution of Acute MIEvolution of Acute MIEvolution of Acute MIEvolution of Acute MI


Acute MI Anterior wallAcute MI Anterior wallAcute MI Anterior wallAcute MI Anterior wall


Anterio-septal MI with RBBBAnterio-septal MI with RBBBAnterio-septal MI with RBBBAnterio-septal MI with RBBB


Extensive Anterio-lateral MIExtensive Anterio-lateral MIExtensive Anterio-lateral MIExtensive Anterio-lateral MI


Fully Evolved MI AnterioseptalFully Evolved MI AnterioseptalFully Evolved MI AnterioseptalFully Evolved MI Anterioseptal


MI inferio-posteriorMI inferio-posteriorMI inferio-posteriorMI inferio-posterior


Inferio-posterior MI with RV MIInferio-posterior MI with RV MIInferio-posterior MI with RV MIInferio-posterior MI with RV MI


Risk Factors for Atherosclerotic Disease

Hoeg JM. JAMA. 1997;277:1387–1390.

Non-modifiable

Age Family history Sex

Modifiable

Cigarette smoking

Diabetes mellitus

Hyperlipidemia Hypertension Obesity Physical

inactivity


Vascular Endothelium

• Endothelium as an organ – 1 to 6 x 1013 cells monolayer

– weighs 1 kg

– covers 6 tennis courts

• Modulator of vascular tone– nitric oxide (NO)

– prostaglandin I2 (PGI2, prostacycline)

• Regulator of hemostasis– antithrombotic

– prothrombotic

Anticoagulant:•GAGs/AT III•TFPI•Thrombomodulin

Profibrinolytic:•t-PA•u-PA•Binding sites for plasminogen•PA receptors

Platelet inhibitory:•PGI2 (prostacycline)•Nitric oxide•ADPase•Carbon monoxide

Procoagulant:•Tissue factor•Binding sites for coagulation factors and fibrin

Antifibrinolytic:•PAI•TAFI

Platelet activating:•vWF•PAF•Fibronectin

•Endothelin-1•TXA2

AntithromboticVasodilation

ProthromboticVasoconstriction


ACUTE CORONARY SYNDROMEACUTE CORONARY SYNDROME

No ST ElevationNo ST Elevation ST ElevationST ElevationST ElevationST Elevation

Unstable AnginaUnstable AnginaNQMI QwMI

Myocardial Infarction

NQMI QwMI Myocardial Infarction

NSTEMINSTEMI


ACUTE CORONARY SYNDROMES (ACS)


ThrombosisThrombosis

ThrombosisThrombosis

Mechanical ObstructionMechanical Obstruction

Mechanical ObstructionMechanical Obstruction

DynamicObstructionDynamicObstruction

DynamicObstructionDynamicObstruction

Inflammation/InfectionInflammation/Infection

Inflammation/InfectionInflammation/Infection

MVO2 MVO2

MVO2 MVO2

Braunwald, Circulation 98:2219, 1998Braunwald, Circulation 98:2219, 1998

..

..

CAUSES OF UA/NSTEMICAUSES OF UA/NSTEMI


ED MANAGEMENT OF UA/NSTEMI

ED MANAGEMENT OF UA/NSTEMI

No recurrent pain;Neg follow-up studies

Nondiagnostic ECGNormal serum cardiac markers

ObserveFollow-up at 4-8 hours: ECG, cardiac markers

Neg: nonischemicdiscomfort;low-risk UA/NSTEMI

YESNO

ST and/or T wave changesOngoing pain

+ cardiac markersHemodynamic abnormalities

Recurrent ischemic pain or+ UA/NSTEMI follow-up studies

Diagnosis of UA/NSTEMIconfirmed

ADMIT+ UA/NSTEMI confirmed

Outpatient follow-up

Evaluatefor

Reperfusion

ST ?

Stress study to provoke ischemia prior to discharge

or as outpatient


INITIATION OF ATHEROCLEROSIS


TYPES OF PLAQUESTYPES OF PLAQUESMedia

- T-Lymphocyte- Macrophage- Foam cell- Activated intimal SMC

“Vulnerable” Plaque

“Stable” Plaque

Lumen

Lumen

Lipid Core

Fibrous Cap


PATHOGENESISPATHOGENESIS

• Normally a fine balance exists between production of collagen by smooth muscle cell & break down

• Impaired gene expression disturbs this balance

Molecular BasisMolecular Basis


PATHOGENESIS OF ACSPATHOGENESIS OF ACS


Vulnerable Plaque

Thin fibrous capThin fibrous cap

LumenLumen

Inflammatory infiltrateInflammatory infiltrate

PlaquePlaque

Large lipid coreLarge lipid core

Spontaneous or triggered ruptureSpontaneous or

triggered rupture

Non occlusive thrombusNon occlusive thrombus Occlusive thrombusOcclusive thrombus

TRIGGERS OF PLAQUE RUPTURE

TRIGGERS OF PLAQUE RUPTURE


Non occlusive thrombusNon occlusive thrombus Occlusive thrombusOcclusive thrombus

Factors limiting thrombosis

Factors limiting thrombosis

Factors favoring thrombosis

Factors favoring thrombosis

• Minor plaque disruption

• High flow•

fibrinolytic activity

• Minor plaque disruption

• High flow•

fibrinolytic activity

• Silent• Unstable

angina• Non-Q-wave

MI• Sudden death

• Silent• Unstable

angina• Non-Q-wave

MI• Sudden death

• Q-wave MI

• Sudden death

• Q-wave MI

• Sudden death

• Major plaque disruption

• Vasospasm low flow

• fibrinolytic activity

• Procoagulant state, such as fibrinogen, factor VII

• platelet ractivity

• Major plaque disruption

• Vasospasm low flow

• fibrinolytic activity

• Procoagulant state, such as fibrinogen, factor VII

• platelet ractivity


ACUTE CORONARY SYNDROME

ACUTE CORONARY SYNDROME

Triggering activities of patients

Triggering activities of patients

Acute Risk Factors of an Arterial Pressure surge or Vasoconstriction

lead to Plaque Disruption

Acute Risk Factors of an Arterial Pressure surge or Vasoconstriction

lead to Plaque Disruption

Acute Risk Factors of a coagulability Increase or Vasoconstriction lead to

complete occlusion by Thrombus

Acute Risk Factors of a coagulability Increase or Vasoconstriction lead to

complete occlusion by Thrombus

Minor Plaque Disruption

Minor Plaque Disruption

Non-Occlusive Thrombus

Non-Occlusive Thrombus

OcclusiveThrombusOcclusiveThrombus

Myocardial Infarction or

Sudden Cardiac Death

Myocardial Infarction or

Sudden Cardiac Death

Asymptomatic Unstable Angina

or Non-Q-MI

Asymptomatic Unstable Angina

or Non-Q-MI

Major Plaque Disruption

Major Plaque Disruption

OcclusiveThrombusOcclusiveThrombus

Non-Vulnerable Atherosclerotic

Plaque

Non-Vulnerable Atherosclerotic

Plaque

Vulnerable Atheroscleroti

c Plaque

Vulnerable Atheroscleroti

c Plaque


UNSTABLE PLAQUE

UNSTABLE PLAQUE


LARGE NON OCCLUDING THROMBUS DUE TO ENDOTHELIAL

EROSION

LARGE NON OCCLUDING THROMBUS DUE TO ENDOTHELIAL

EROSION


NON OCCLUDING THROMBUS DUE TO PLAQUE RUPTURE

NON OCCLUDING THROMBUS DUE TO PLAQUE RUPTURE


OCCLUSIVE THROMBUS DUE TO PLAQUE RUPTURE

OCCLUSIVE THROMBUS DUE TO PLAQUE RUPTURE


HEALED PLAQUEHEALED PLAQUE


PLATELET PLUG FORMATION

PLATELET PLUG FORMATION

ADPADP EpinephrineEpinephrine ThrombinThrombinAdhesion CollagenAdhesion Collagen

Arachidonic Acid releaseArachidonic Acid releaseRelease of ADP,

serotoninRelease of ADP,

serotonin

Thromboxane A2Thromboxane A2

GP IIb/IIIa exposureGP IIb/IIIa exposure

Platelet aggregationPlatelet aggregation

GP IIb/IIIa receptor blockersGP IIb/IIIa receptor blockers

AspirinAspirin

Ticlopidine / ClopidogrelTiclopidine / Clopidogrel


GP IIb/IIIa (quiescent)

GP IIb/IIIa (activated)

Resting Platelet Activated Platelet


GP IIb/IIIa (activated)

Platelet R.G.D.Sequence

vWF

Fibrinogen


Competitive Antagonist(Integrilin, Aggrastat)

Activated Platelet


Thrombotic Process — Pathophysiology

Plaque Characteristics & Disruption

Thrombotic Process — Pathophysiology

Plaque Characteristics & Disruption

Lumen

ThinningLipid-Rich

Core

Fibrous Cap Disruption

Thrombus

Fibrous Cap


Production of LMWH by depolymerization of unfractionated

heparinNative heparin Depolymerisation processDepolymerisation process LMWHLMWH

Pentasaccharide sequence Semin Thromb. Hemost. 1993; 19 suppl. 1: 1-11


MODE OF ACTION OF HEPARIN AND LMWHMODE OF ACTION OF HEPARIN AND LMWH


Fibrinogen

Vessel Wall Injury

Vessel wall

Platelet

GP IIb, IIIa

ECPlatelet

Lumen

ADP Receptor

CLOPIDOGREL

TXA2

ADP

Cyclooxygenase

ASPIRIN

Arachidonic Acid

PGH2 TXA2

ADP

IIB IIIa

MODE OF ACTION OF ANTIPLATELET AGENTS


ANTI-PLATELET THERAPY


Antiplatelet AgentsGP IIb/IIIa InhibitorsAntiplatelet Agents

GP IIb/IIIa Inhibitors

Fibrinogen

GP IIb/IIIaReceptor

GP IIb/IIIaInhibitors


Oral Antiplatelet AgentsOral Antiplatelet Agents

Mechanism of ActionMechanism of Action

CollagenCollagenThrombinThrombin

TXATXA22

ADPADP

(Fibrinogen(FibrinogenReceptor)Receptor)

ADP = adenosine diphosphate, TXAADP = adenosine diphosphate, TXA22 = thromboxane A = thromboxane A22, COX = , COX =

cyclooxygenase. Schafer AIcyclooxygenase. Schafer AI. Am J Med. Am J Med.. 1996;101:199–209.1996;101:199–209.

clopidogrel bisulfateclopidogrel bisulfate

TXATXA22

ADPADP

dipyridamoledipyridamole

phosphodiesterasephosphodiesterase

ADPADP

Gp IIb/IIIaGp IIb/IIIa ActivationActivation

COXCOX

ticlopidine HClticlopidine HCl

aspirinaspirin


AnticoagulantsDirect Thrombin InhibitorsHirudin-Thrombin Binding

AnticoagulantsDirect Thrombin InhibitorsHirudin-Thrombin Binding

Mechanisms of Thrombin Inhibition

Fibrin

Thrombin Thrombin Thrombin

Substrate Recognition Site

Fibrin Binding Site

CatalyticSite

Hirudin

ATIII/Heparin

Fibrin


The Management of Patients with Acute Myocardial Infarction

Initial Assessment

and Evaluation


Algorithm for Initial Assessment and Evaluation of the Patient with Acute Chest Pain

Within 10 minutes

• Initial evaluatioon • 12 lead ECG• Establish IV • Aspirin 160-325 mg - chewed • Establish continuous ECG monitoring • Blood for baseline serum cardiac markers

Chest pain consistent with coronary ischemia

Therapeutic/Diagnostic tracking according 12-lead ECG

ECG suggestive of ischemia -T wave inversion or ST depression

ST segment elevation or newbundle branch block

Nondiagnostic / normal ECG


Emergency Department Algorithms/Protocolfor Patients with Symptoms and Signs of AMI

Onset ofsymptoms

Ambulance presentspatient to ED lobby

Patient presents to ED lobby

ED triage or charge nurse triages patient • AMI symptoms and signs • 12-lead ECG • Brief, targeted history

Emergency nurse initiates emergencynursing care in acute care area of ED • Cardiac monitor • Blood studies • Oxygen therapy • Nitroglycerin • IV D5W • Aspirin

Emergency Physicianevaluates patient • History • Physical exam • Interpret ECG

AMIpatient?


Emergency Department Algorithms/Protocolfor Patients with Symptoms and Signs of AMI

Release

Consult

Evaluatefurther

Conduct education andfollow-up instruction

AMIpatient?

Candidatefor fibrinolytic

therapy

Fibrinolytictherapy

Other indicated treatment:

• Other drugs for AMI (beta-blockers, heparin, aspirin, nitrates)• Transfer to cath lab for PTCA or surgery for CABG

Admit

Uncertain

Trans Mural

Yes No

Yes

No


Patient with Acute Chest Pain withnon-diagnostic and normal ECG

• Continue evaluation/monitoring in Emergency Department or Chest Pain Unit• Serial serum cardiac marker levels - CKMB, Trop • Serial ECGs• Consider noninvasive evaluation of ischemia• Consider alternative diagnoses

Non-diagnostic / normal ECG

No Evidence of MI or ischemia

MI or demonstrable

ischemia

Discharge withfollow-up asappropriate

(Goal: 12-24 hours)

Admit to unit ofappropriate intensity


Patient with Acute Chest Pain withT-wave inversion or ST depression

• Anti-ischemia Therapy• Analgesia

Admit to unit ofappropriate intensity

ECG suggestive of ischemia -T wave inversion or ST depression

Admission blood work• CBC• Electrolytes, BUN, creatinine• Lipid profile

Differential diagnosis• ischemia

• acute posterior MI

• ventricular hypertrophy

• digoxin effect

• pericarditis

• pulmonary embolus

• LBBB

• hyperventilation

• anxiety

• normal variants


Management of Patients with Non-ST Elevation MI

ST depression/T-wave inversion:Suspected AMI

Heparin + AspirinNitrates for recurrent angina

Assess Clinical Status

Continued observationin hospital

Consideration ofstress testing

PCICABG

NoYes

Antithrombins: LMWH - high-risk patientsAnti-Platelets: GpIIb/IIIa inhibitor

Patients without prior beta-blocker therapy or

who are inadequatelytreated on current dose

of beta-blocker

Persistnet symptoms inpatients with prior

beta-blocker therapy orwho cannot tolerate

beta-blockers

Establish adequate beta-blockade

Add calcium antagonist

High-risk patient:1. Recurrent ischemia2. Depressed LV function3. Widespread ECG changes4. Prior MI

Clinical stability

Catheterization: Anatomysuitable for revascularization

MedicalTherapy

Modified from Antman EM. Atlas of Heart Disease, VIII; 1996


Patient with Acute Chest Pain withST elevation or new bundle branch block

Assess suitability for reperfusion• ? Contraindications for fibrinolysis• Availability and appropriateness of primary angioplastyInitiate anti-ischemia therapy• Beta-blocker• NitroglycerineAnalgesia

ST segment elevation or newbundle branch block

Initiate fibrinolysis if indicated

Goal: 30 minutes from entry to ED

Primary PTCAif available and suitable

Goal: PTCA within 90 30 minutes

Admission blood work

Admit - CCU



Initial Management


Management of Patients with ST Elevation

ST elevation

12 h

AspirinBeta-blocker

Eligible forfibrinolytic therapy

> 12 h

Fibrinolytic therapycontraindicated

Not a candidate forreperfusion therapy

Persistent symptoms ?

Fibrinolytic therapyPrimary

PTCA or CABG

Other medical therapy:ACE inhibitors

? NitratesAnticoagulants

ConsiderReperfusion

Therapy

No Yes

Modified from Antman EM. Atlas of Heart Disease, VIII; 1996


Comparison of Approved Fibrinolytic Agents

Streptokinase Anistreplase Alteplase Reteplase

Dose 1.5 MU 30 mg 100 mg 10U x 2 in 30-60 min in 5 min in 90 min over 30

min

Bolus administration NO Yes No Yes

Antigenic Yes Yes No No

Allergic reactions Yes Yes No No

(mostly hypotension)

Systemic fibrinogen Marked Marked Mild Moderate

depletion

90-min patency rate ~50% ~65% ~75% ~75%

TIMI-3 flow 32% 43% 54% 60%

Mortality rate 7.3% 10.5% 7.2% 7.5%

Cost /dose (US) $294 $2116 $2196 $2196


ContraindicatIons and Cautions for Fibrinolytic Used in Myocardial

Infarction

Absolute Contraindications:

• Previous hemorrhagic stroke at any time: other strokes or cerebrovascular events within one year

• Known intracranial neoplasm

• Active internal bleeding (does not include menses)

• Suspect aortic dissection


ContraindicatIons and Cautions for Fibrinolytic Used in Myocardial

Infarction

• Severe uncontrolled HTN on presentation (BP >180/110 mmHg)

• History of prior CVA or known intra-cerebral pathology not covered in contraindications

• Current use of anticoagulants in therapeutic doses (INR 2-3); no bleeding diathesis

• Recent trauma (within 2-4 weeks) including head trauma

• Noncompressible vascular punctures

• Recent (within 2-4 weeks) internal bleeding

• For streptokinase/anistreplase: prior exposure (especially within 5d-2 yrs) or prior allergic reaction

• Pregnancy

• Active peptic ulcer

• History of chronic hypertension

Cautions / Relative Contraindications


Primary Percutaneous Transluminal Coronary Angioplasty Recommendations

Class I Recommendations

1. As an alternative to fibrinolytic therapy if:– ST segment elevation or new or presumed new LBBB

– Within 12 hrs of symptoms or > 12 hrs of persistent pain

– In a timely fashion (90 30 min)

– By experienced operators

– In appropriate environment

2. In cardiogenic shock patients < 75 yrs or within 36 hrs of AMI and revascularization can be performed within 18 hrs of onset of shock

Class IIa Recommendations

1. As reperfusion strategy in candidates for reperfusion who have contraindications to fibrinolytic therapy


Primary Percutaneous Transluminal Coronary Angioplasty Recommendations

Class IIb Recommendations

1. In patients with AMI who do not present with ST elevation but who have reduced (< TIMI grade 2) flow of the infarct-related artery and when angioplasty can be performed within 12 hrs of onset of symptoms

Class III Recommendations

1. This classification applies to patients with AMI who:• undergo elective angioplasty in the non-infarct-related artery at the time of AMI

• are beyound 12 hrs after the onset of symptoms and have no evidence of myocardial ischemia

• have received fibrinolytic therapy and have no symptoms of myocardial ischemia

• are fibrinolytic-eligible and are undergoing primary angioplasty by and unskilled operator in a laboratory that does not have surgical capability


Advantages of Fibrinolytic Therapy

• More universal access• Shorter time to treatment• Greater clinical trial evidence of:

– reduction in infarct size

– improvement of LV function

• Results less dependent on physician experience• Lower system costs


Advantages of Primary PTCA

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


Pharmacologic Management of Patients with MI

Heparin RecommendationsClass I Recommendations

1. In patients undergoing percutaneous or surgical revascularization


1. Intravenously in patients undergoing reperfusion therapy with alteplase/reteplase (note change in recommendations)

1999 1996

Bolus Dose 60 U/kg 70 U/kgMaintenance ~12 U/kg/hr ~15 U/kg/hrMaximum 4000 U bolus None

1000 U/h if >70kgaPTT 1.5-2.0 x control 1.5-2.0 x control

(50-70 sec) for 48 hrs (50-70 sec) for 48 hrs



Heparin RecommendationsClass IIa Recommendations (continued)

2. Intravenous unfractionated heparin (UFH) or low molecular weight heparin (LMWH) subcutaneously for patients with non-ST elevation MI

3. Subcutaneous UFH (eg, 7,500 U b.I.d.) or low molecular weight heparin (eg, enoxaparin 1 mg/kg b.I.d.) in all patients not treated with fibrinolytic therapy who do not have a contraindication to heparin. In patients who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus), intravenous heparin is prefered

4. Intravenously in patients treated with nonselective fibrinolytic agents (streptokinase, anistrplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus)



Heparin RecommendationsClass IIb Recommendations

1. In patients treated with nonselective fibrinolytic agents, not at high risk, subcutaneous heparin, 7,500 U to 12,500 U twice a day until completely ambulatory


1. Routine intravenous heparin within 6 hrs to patients receiving a nonselective fibrinolytic agent (streptokinase, anistrplase, urokinase) who are not at high risk for systemic embolism



GP IIb/IIIa Inhibitors - New Recommendations


1. For use in patients experiencing an MI without ST segment elevation who have some high-risk features and/or refractory ischemia, provided they do not have a contraindication due to a bleeding risk


Classification of Inotropic Agents

Agent Mechanism Inotrpic Vascular Effect Major Use

Isoproterenol -1 receptor ++ Dilatation Hypotension due tobradycardia;no pacing available

Dobutamine -1 receptor ++ Mild dilatation Low output with SBP >90 mm Hg

Dopamine Low dose: ++ Renovascular dilatation Hypoperfusion with SBP <90 mm Hg

(dopaminergic) or 30 mm Hg below usual value Medium dose: (-1 receptor) Constriction High dose: (-receptor) Intense constriction

Norepinephrine - receptor ++ Intense constriction Extreme hypotension despitedopamine use

Amrinone PDE inhibitor ++ Dilatation Second-tier agent after failure ofdopamine / dobutamine

Milrinone PDE inhibitor ++ Dilatation

Digitalis Inhibts Na+-K+ + Variable Established systolic LV dysfunction pump and symptoms of heart failure for

chronic therapy



Hospital Management


Sample Admitting Orders

Condition Serious

IV NS or D5W to keep vein open

Vital signs q 1/2 hr until stable, the q 4 hrs and p.r.n.Notify if HR <60 or >110; BP <90 or >150;RR <8 or >22. Pulse oximetry x 24 hrs

Activity Bed rest with bedside commode and progress astolerated after approximately 12 hrs

Diet NPO until pain free, then clear liquids.

Progress to a heart - healthy diet

Medications Nasal O2 2 L/min x 3 hrsEnteric-coated aspirin daily (165 mg)Stool softener dailyBeta-adrenoreceptor blockers

Consider need for analgesics, nitroglycerin, anxiolytic


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)


Treatment Strategy for Right Ventricular Ischemia/Infarction

• Maintain right ventricular preload– Volume loading (IV normal saline)

– Avoid use of nitrates and diuretics

– Maintain AV synchrony (AV sequential pacing for symptomatic high-degree heart block unresponsive to atropine)

– Prompt cardioversion for hemodynamically significant SVT

• Inotropic support– Dobutamine (if cardiac output fails to increase after volume

loading)


Treatment Strategy for Right Ventricular Ischemia/Infarction

• Reduced right ventricular afterload with LV dysfunction– Intra-aortic balloon pump

– Arterial vasodilators (sodium nitroprusside, hydralazine)

– ACE inhibitors

• Reperfusion– Fibrinolytic agents

– Primary PTCA

– CABG (in selected patients with multivessel disease)


Clinical Profile of MechanicalComplications of Myocardial Infarction

Variable Ventricular Free Wall Paillary MuscleSeptal Defect Rupture Rupture

Age (mean, years) 63 69 65

Days post MI 3-5 3-6 3-5

Anterior MI 66% 50% 25%

New Murmur 90% 25% 50%

Palpable thrill Yes No Rare

Previous MI 25% 25% 30%

Echo: 2-D Visualize defect May have PE Flail or prolapsing leaflet Doppler Detect shunt Regurgitating jet in LA

PA catheterization Oxygen step up Equalization of Prominent V-wave in Hi RV diastolic pressure PCW tracing

Mortality: Medical 90% 90% 90%Surgical 50% Case report 40-90%

Modified from Labovitz AJ, et al. Cardiovasc Rev Rep. 1984; 5-948



MI Management Summary


Initial Management in ED

• Initial evaluation with 12-lead ECG in < 10 minutes

– targeted history (for AMI inclusion, thrombolysis exclusion)

– vital signs, focused examination

• Continual ECG, automated BP, HR monitoring

• IV access

• Draw blood for serum cardiac markers, electrolytes, magnesium, hematology, lipid profile panel


Initial Management in ED

• Aspirin165-325 mg (chew and swallow)

• Sublingual NTG unless SBP <90 or HR <50 or >100: test for prinzmetal’s angina, reversible spasm, anti-ischemic, antihypertensive effects

• O2 by nasal prolongs, first 2-3 h in all; continue if PaO2 <90%

• Analgesia: small doses of morphine (2-4 mg) as needed

• Fibrinolysis or PCI if ST elevation > 1mV or LBBB(Goal: door-needle < 30 min or door-dilatation < 60-90 min)


MI Management in 1st 24 Hours

• Limited activity for 12 hours, monitor 24 hours

• No prophylactic antiarrhythmics

• IV heparin if: a) large anterior MI; b) PTCA; c) LV thrombus; or d) alteplase/reteplase use (for ~48 hours)

• SQ heparin for all other MI (7,500 u b.I.d.)

• Aspirin indefinitely

• IV NTG for 24-48 hrs if no / HR or BP

• IV beta-blocker if no contraindications

• ACE inhibitor in all MI if no hypotension


In-Hospital Management

• Aspirin indefinitely

• Beta-blocker indifinitely

• ACE inhibitor (DC at ~6 wks if no LV dysfunction)

• If spontaneous or provoked ischemia - elective cath

• Suspected pericarditis - ASA 650 mg q 4-6 hrs

• CHF - ACE inhibitor and diuretic as needed

• Shock - consider intra-aortic balloon pump + cath with PCI or CABG

• RV MI - fluids (NS) + inotropics if hypotensive


Predictors of 30 day Mortality in Fibrinolysis Patients

GUSTO Trial - 41,021 patients

Age 32%

Systolic BP 24%

Other 10%

AMI Location 6%

Heart rate 12%

Killip class 15%

Circulation 1995; 91:1659-1668

(DM, smoking, BP;Height/Weight, Prior CVD;Time to Rx; Choice of fibrinolytic therapy; US hospital)


Present Absent Absent

Strategy I Strategy II Strategy III

Symptom-Limited Exercise Testat 14-21 Days

Submaximal Exercise Testat 5-7 Days

Markedly Abnormal

Mildly Abnormal

Negative

Exercise Imaging Study

ReversibleIschemia

No ReversibleIschemia

Medical Treatment

CardiacCatheterization

Markedly Abnormal


No Reversible Ischemia

Strenuous Leisure Activity or Occupation

Symptom-Limited Exercise Test at 3-6 Weeks

Markedly Abnormal

Mildly Abnormal

Negative


ReversibleIschemia

No ReversibleIschemia

Medical Treatment

Clinical Indications of High Risk At Predischarge

Mildly Abnormal Negative

Reversible Ischemia


Recommendations for Hormone Replacement Therapy (HRT) After

Acute MIClass IIa Recommendations

1. HRT with estrogen and progestin for secondary prevention of coronary events should not be given de novo to postmenopausal women after AMI

2. Postmenopausal women who are already taking HRT with estrogen plus progestin at the time of AMI can continue their therapy

HERS Study: JAMA 1998;280:605-13


Initial Treatment

• A = Aspirin and Antianginal therapy

• B = Beta-blocker and Blood pressure

• C = Cigarette smoking and Cholesterol

• D = Diet and Diabetes

• E = Education and Exercise


Symptoms Suggestive of ACS

Definite ACS

No ST elevation

Algorithm for the Evaluation and Managementof Patients Suspected of Having an ACS.

ST elevation

Possible ACSChronic Stable AnginaNoncardiac Diagnosis

Treatment as indicated by

alternative diagnosis

See ACC/AHA/ACPGuidelines for Chronic

Stable Angina

Nondiagnostic ECGNormal Initial serum

cardiac markers

ST and/or T wave changesOngoing pain

Positive cardiac markersHemodynamic abnormalities

ObserveFollow-up at 4-8 hours;ECG, cardiac markers

Evaluation forreperfusion therapy

See ACC/AHA Guidelines for

Acute MI

No recurrent pain;Negative follow-up studies

Recurrent ischemic painor positive follow-up studiesDiagnosis of ACS confirmed

Admit to hospitalManage via acute ischemia pathway

Stress study to provoke ischemiaConsider evaluation of LV function if ischemia present

(Test may be performed prior to discharge or as outpatient)

Negative:Potential diagnoses:

nonischemic discomfortlow-risk ACS

Positive:Diagnosis of ACS

confirmed

Arrangement for outpatientfollow-up


III. Hospital Care

A. Anti-ischemic Therapy

B. Antiplatelet and Anticoagulation Therapy

C. Risk Stratification

D. Early Conservative vs. Invasive Strategies


Acute Ischemic Pathway

Recurrent Ischemia and/orST segment shift, or Deep T-wave Inversion,

or Positive cardiac markers

Early Invasive strategy

AspirinBeta-blockers

NitratesAntithrombin regimen

GP IIb/IIIa inhibitorMonitoring (rhythm and ischemia)

Immediateangiography

12-24 hourangiography

Patientstabilizes

Recurrentsymptoms/ischemia

Heart failureSerious arrhythmia

Follow onMedical Rx

EF < .40

Early Conservative strategy

Evaluate LV function

EF .40

Stress Test

Not low risk

Low risk


A. Anti-Ischemic TherapyClass I - Recommendations

1. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection in patients with ongoing rest pain

2. Sublingual follow by intravenous nitroglycerin (NTG) for immediate relief of ischemia and associated symptoms

3. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion is present

4. A beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, in the absence of contraindications



• 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.




Intravenous Thrombolytic Therapy

in Non-ST Elevation MI


D. Early Conservative Versus Invasive Strategies

Class I - Recommendations1. An early invasive strategy is recommended in patients with

UA/NSTEMI and any of the following high-risk indicators:

a. Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemia therapy

b. Elevated TnT or TnI

c. New or presumed new ST-segment depression at presentation

d. Recurrent angian/ischemia with CHF symptoms, an S3 gallop, pulmonary edema, worsening rales, or new or worsening mitral regurgitation.


D. Early Conservative Versus Invasive Strategies

Class I - Recommendationse. High-risk findings on noninvasive stress testing

f. Depressed LV systolic function (eg.ejection fraction [EF] <0.40 on noninvasive study).

g. Hemodynamic instability or angina at rest accompanied by hypotension.

h. Sustained ventricular tachycardia.

i. PCI within 6 months.

j. Prior CABG


IV. Coronary Revascularization

Recommendations for Revascularization with PCI and

CABG in Patients with UA/NSTEMI


Recommendations for Revascularization Class I - Recommendations

1. CABG for patients with significant left main CAD

2. CABG for patients with 3-vessel CAD; the survival benefit is greatest in patients with abnormal LV function (EF <0.50)

3. CABG for patients with 2-vessel CAD with significant proximal left anterior descending CAD and wither abnormal LV function (EF <0.50) or demonstrable ischemia on noninvasive testing



4. PCI or CABG for patients with 1- or 2- vessel CAD without significant proximal left anterior descending CAD but with a large area of viable myocaridum and high-risk criteria on noninvasive testing

5. PCI for patients with multivessel CAD with suitable coronary anatomy, with normal LV function, and without diabetes



6. CABG with the internal mammary artery for patients with multivessel CAD and treated diabetes mellitus

7. Intravenous platelet GP IIb/IIIa inhibitor in UA/NSTEMI patients undergoing PCI


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)

Agency for Health Care Policy Research - 1994Canadian Cardiovascular Society Classification


Unstable Anginapathogenesis

• Plaque disruption

• Acute thrombosis

• Vasoconstriction



• Plaque disruption– Passive plaque disruption

soft plaque with high concentration of cholesteryl esters and a thin fibrous cap

– Active plaque disruptionmacrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture



• Acute Thrombosis– Vulnerable plaque

• disrupted plaque with ulceration

• occurring in 2/3 of unstable patients

• the exposed lipid-rich core abundant in cholesteryl ester is highly thrombogenic

– Systemic Hypercoagulable State• disrupted plaque with erosion

• occurring in 1/3 of unstable patients



• Vasoconstriction– the culprit lesion in response to deep arterial

damage or plaque disruption– area of dysfunctional endothelium near the

culprit lesion– platelet-dependent and thrombin-dependent

vasoconstriction, mediated by serotonin and thromboxane A2


Acute Coronary Syndrome

• Process of resolution– spontaneous thrombolysis– vasoconstriction resolution– presence of collateral circulation

• Delayed or absence of resolution may lead to non-Q-wave or Q-wave myocardial infarction


Non-Q-Wave MIclues to diagnosis

• Prolonged chest pain

• Associated symptoms from the autonomic nervous system– nausea, vomiting, diaphoresis

• Persistent ST-segment depression after resolution of chest pain


Prinzmetal’s Anginaclues to diagnosis

• Transient ST-segment elevation during chest pain

• Intermittent chest pain– often repetitive– usually at rest– typically in the early morning hours– rapidly relieved by nitroglycerine

• Syncope (rare), Raynaud’s, migraine


Unstable AnginaAnti-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 InvestigatorsCirculation 1994; 89:1545-1556


• Discharge prescription details

Recommendations for Revascularization

Class I - Recommendations


Fibanincidence of intracranial bleeding

Treatment (%)

Study Compound Placebo Active Heparin

RESTORETirofiban 0.3 0.1

EPIC Abciximab 0.3 0.1

0.4

EPILOG Abciximab 0.0 0.1

IMPACT II Integrelin 0.07 0.07 0.15

The EXCITE Trial Investigators

Bolus

Low dose

High dose

Bolus + Infusion


Unstable AnginaAnti-platelet Therapy

• Summary

The question is no longer“Is there a reason to use GP IIb/IIIa inhibitors?” but “Is there a reason not to use them?”

Eric Topol, MD


Unstable AnginaAnti-coagulant Therapy

• Heparin– recommendation is based on documented

efficacy in many trials of moderate size– meta-analyses (1,2) of six trials showed a 33%

risk reduction in MI and death, but with a two fold increase in major bleeding

– titrate PTT to 2x the upper limits of normal

1. Circulation 1994;89:81-882. JAMA 1996;276:811-815


Unstable AnginaAnti-coagulant Therapy

• Low-molecular-weight heparinadvantages over heparin:– better bio-availability

– higher ratio (3:1) of anti-Xa to anti-IIa activity

– longer anti-Xa activity, avoid rebound

– induces less platelet activation

– ease of use (subcutaneous - qd or bid)

– no need for monitoring


Unstable Angina Anti-coagulant Therapy

• Low-molecular-weight heparin– ESSENCE Trial (Efficacy and Safety of

Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study)

– at 30days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin

N Eng J Med 1997;337:447-452

[email protected]@worksAdapted from Weaver WD, et al. JAMA. 1993;270:1211-1216.

1.2

8.7

4.9

11.2

0.0

2.0

4.0

6.0

8.0

10.0

12.0

Mortality Infarct Size

Tx <70 minutesfrom onset

Tx >70 minutesfrom onset

PP=0.04=0.04PP=0.04=0.04 PP<0.001<0.001PP<0.001<0.001

Pe

rce

nt

MITI: Mortality, Infarct Size, and Time


1.0

3.74.0

6.4

14.1

0

5

10

15

20

25

60 61-75 76-90 91

Berger PB, et al. Circulation. 1999;100:14-20.

PP=0.00=0.0011

PP=0.00=0.0011

Door-to-Balloon Time (minutes)

Importance of Door-to-Balloon Time:

30-Day Mortality in the GUSTO-IIb Cohort

Mo

rta

lity

(%)

>< PTCA not performed

Patency and Mode of ReperfusionPatency and Mode of ReperfusionPatency and Mode of ReperfusionPatency and Mode of Reperfusion

0

20

40

60

80

100

0 30 45 60 75 90 120 150

Pate

ncy

Rat

e (%

)

Fibrinolysis

PTCA at 75minutes

PTCA at 120minutes

Time (minutes)Time (minutes)

90-minutepatency

90-minutepatency

ED

arrival

ED

arrival

Drug

administration

Drug

administration

Adapted from Gibson CM. Ann Intern Med. 1999;130:841-847.


Time of OnsetTime of OnsetTime of OnsetTime of Onset

ED Time Point 1: ED Time Point 1: DOORDOOR

ED Time Point 1: ED Time Point 1: DOORDOOR

ED Time Point 2: ED Time Point 2: DATADATA

ED Time Point 2: ED Time Point 2: DATADATA

ED Time Point 3: ED Time Point 3: DECISIONDECISION

ED Time Point 3: ED Time Point 3: DECISIONDECISION

ED Time Point 4: ED Time Point 4: DRUGDRUG

ED Time Point 4: ED Time Point 4: DRUGDRUG

Time Interval IIIDecision to drug

Time Interval IIECG to decision to treat

Time Interval IDoor to ECG

NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997:97-3787.

The Four Ds


ST-segment elevationST-segment elevationST-segment elevationST-segment elevation

Aspirin, beta-blocker, antithrombinAspirin, beta-blocker, antithrombinAspirin, beta-blocker, antithrombinAspirin, beta-blocker, antithrombin

12 h12 h12 h12 h >12 h>12 h>12 h>12 h

Eligible for Eligible for fibrinolytic fibrinolytic

therapytherapy

Eligible for Eligible for fibrinolytic fibrinolytic

therapytherapy

FibrinolyticFibrinolytictherapy therapy

contraindicatedcontraindicated

FibrinolyticFibrinolytictherapy therapy

contraindicatedcontraindicated

Not a candidate Not a candidate for reperfusion for reperfusion

therapytherapy

Not a candidate Not a candidate for reperfusion for reperfusion

therapytherapyPersistent Persistent

symptoms?symptoms?Persistent Persistent

symptoms?symptoms?

FibrinolyticFibrinolytictherapytherapy

FibrinolyticFibrinolytictherapytherapy

Primary PTCA or Primary PTCA or CABGCABG

Primary PTCA or Primary PTCA or CABGCABG

NoNoNoNo YesYesYesYes

Other medical therapy: Other medical therapy: ACE inhibitors? NitratesACE inhibitors? NitratesOther medical therapy: Other medical therapy:

ACE inhibitors? NitratesACE inhibitors? Nitrates

Consider Consider reperfusion reperfusion

therapytherapy

Consider Consider reperfusion reperfusion

therapytherapyPTCA, 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 http://www.acc.org/clinical/guidelines and http://www.americanheart.org. Accessed February 2000.

ACC/AHA Guidelines for the Management of Patients With

AMI

http://www.acc.org/clinical/guidelines


Summary: Importance of Early Treatment

• Prompt reperfusion limits myocardial necrosis, preserves left ventricular function, and reduces mortality

• Achievement of early, complete reperfusion may be more feasible with fibrinolytic therapy than with primary PTCA

• Maximal benefits of fibrinolytic therapy are attained within the first hour of symptom onset, although benefits extend out to 12 hours

• Continued efforts are needed to minimize door-to-drug time

Myocardial InfarctionMyocardial Infarction

OverviewOverview

• Estimated 200-300,000 sudden (out-of-hospital) Estimated 200-300,000 sudden (out-of-hospital) deaths per year in U.S.deaths per year in U.S.

• Approximately 1 million hospitalizations per year in Approximately 1 million hospitalizations per year in U.S.U.S.

• Absolute number of MI events and fatality rates Absolute number of MI events and fatality rates decliningdeclining

• Remains principal cause of death in Western worldRemains principal cause of death in Western world

Acute MIAcute MI

Impact of Modern Critical Care on MortalityImpact of Modern Critical Care on Mortality

Adapted from Antman, Braunwald In:Braunwald ed. Heart Disease p 1184.Adapted from Antman, Braunwald In:Braunwald ed. Heart Disease p 1184.

Pre-CCUEra

Pre-CCUEra

CCUEra

CCUEra

ReperfusionEra

ReperfusionEra

00

1010

2020

3030

4040Short-Term Mortality (%)Short-Term Mortality (%)

3030

1515

6.56.5

DefibrillationHemodynamic

Monitoring-Blockers Aspirin

ThrombolysisPTCA

Management of Acute MIManagement of Acute MI

DiagnosisDiagnosis

Risk StratificationRisk Stratification

Acute TherapyAcute Therapy ReperfusionReperfusion AdjunctiveAdjunctive

ComplicationsComplications

Pre-Discharge Pre-Discharge ManagementManagement

Diagnosis of Acute MIDiagnosis of Acute MI

HistoryHistory

• Classic symptoms: intense, oppressive Classic symptoms: intense, oppressive chest pressure radiating to left armchest pressure radiating to left arm

• Other symptoms:Other symptoms: chest heaviness, burningchest heaviness, burning radiation to jaw, neck, shoulder, back, radiation to jaw, neck, shoulder, back,

armsarms nausea, vomitingnausea, vomiting diaphoresisdiaphoresis dyspneadyspnea lightheadednesslightheadedness

• Symptoms may be mild or subtleSymptoms may be mild or subtle


Physical ExaminationPhysical Examination

• Tachycardia or bradycardiaTachycardia or bradycardia

• ExtrasystolesExtrasystoles

• SS33 or S or S44, mitral regurgitation , mitral regurgitation

murmurmurmur

• Lung ralesLung rales

• Hypertension or hypotensionHypertension or hypotension

• Pallor, distressPallor, distress


ElectrocardiogramElectrocardiogram

Defines location, extent, and prognosis of Defines location, extent, and prognosis of infarctioninfarction

• ST elevation diagnostic of coronary ST elevation diagnostic of coronary occlusionocclusion

• Q-waves do NOT signify completed infarctionQ-waves do NOT signify completed infarction

• ST depression or T inversion: unlikely total ST depression or T inversion: unlikely total coronary occlusioncoronary occlusion

• ST elevation in RVST elevation in RV44 for RV infarction for RV infarction

• Observe up to 24 hrs for non-diagnostic ECGObserve up to 24 hrs for non-diagnostic ECG

• Differentiate from early repolarization in VDifferentiate from early repolarization in V1-21-2

<4<4 4-74-7 8-118-11 12-1512-15 >16>1600

2020

4040

6060

8080

100100

Time to Peak CK Activity (hrs)Time to Peak CK Activity (hrs)

Occl -Reperf

Occl +Reperf

Subtot Occl

Acute MIAcute MI

Myocardial EnzymesMyocardial EnzymesTroponinTroponin

Ohman et al. NEJM 1996;335:1333.Ohman et al. NEJM 1996;335:1333.

CK-MB>7CK-MB>7 CK-MB<7CK-MB<700

55

1010

1515

2020% of Patients% of Patients

11.611.6

2.32.3

12.312.3

4.14.1

TnT >0.1 ng/ml

TNT <0.1 ng/ml

CPKCPK

Gore et al. AJC 1987;59:1234. Gore et al. AJC 1987;59:1234.


EchocardiographyEchocardiography

• Not diagnostic, but supportiveNot diagnostic, but supportive

• Identify regional wall motion abnormalitiesIdentify regional wall motion abnormalities

• Absence of contralateral wallAbsence of contralateral wall hyperkinesia hyperkinesia suggests multivessel disease or IRA suggests multivessel disease or IRA recanalizationrecanalization

• Assess LV function, prior infarctsAssess LV function, prior infarcts

• More sensitive than ECG for RV infarctionMore sensitive than ECG for RV infarction


Differential DiagnosisDifferential Diagnosis

Ischemic Heart DiseaseIschemic Heart Disease• angina, aortic stenosis, hypertrophic CMPangina, aortic stenosis, hypertrophic CMP

Nonischemic Cardiovascular DiseaseNonischemic Cardiovascular Disease• pericarditis, aortic dissectionpericarditis, aortic dissection

GastrointestinalGastrointestinal• esophageal spasm, gastritis, PUD, esophageal spasm, gastritis, PUD,

pancreatitis, cholecystitispancreatitis, cholecystitis

PulmonaryPulmonary• pulmonary embolism, pneumothorax, pulmonary embolism, pneumothorax,

pleurisypleurisy


Coronary AngiographyCoronary Angiography

• May be necessary for equivocal symptoms May be necessary for equivocal symptoms and ECGand ECG

e.g. patients with prior CABG, previous MI, e.g. patients with prior CABG, previous MI, myocarditis with diffuse ECG myocarditis with diffuse ECG ’s, non-’s, non-characteristic characteristic ’s on ECG’s on ECG

• Finding of acutely-occluded vessel diagnosticFinding of acutely-occluded vessel diagnostic

• Allows mechanical reperfusionAllows mechanical reperfusion

Acute MIAcute MI

Coronary AngiographyCoronary Angiography

• Incorporated in primary, rescue PTCA Incorporated in primary, rescue PTCA strategiesstrategies

• If If ischemia, spontaneous or exercise- ischemia, spontaneous or exercise-induced or complicated (CHF, arrhythmia)induced or complicated (CHF, arrhythmia)

• Controversial if uncomplicated MIControversial if uncomplicated MI

• Delineates anatomy but may potentiate Delineates anatomy but may potentiate unneeded revascularizationunneeded revascularization

• Very low risk but appreciable costVery low risk but appreciable cost

• Key prognostic indicatorKey prognostic indicator


DiagnosisDiagnosis





Acute MI - Risk StratificationAcute MI - Risk Stratification

The GUSTO Pyramid - 30 Day Mortality ModelThe GUSTO Pyramid - 30 Day Mortality Model

Age (31%)Age (31%)Age (31%)Age (31%)

Systolic Blood Pressure (24%)Systolic Blood Pressure (24%)Systolic Blood Pressure (24%)Systolic Blood Pressure (24%)Killip Class (15%)Killip Class (15%)Killip Class (15%)Killip Class (15%)

Heart Rate (12%)Heart Rate (12%)Heart Rate (12%)Heart Rate (12%)MI Location (6%)MI Location (6%)MI Location (6%)MI Location (6%) Prior MI (3%)Prior MI (3%)Prior MI (3%)Prior MI (3%)Age x Killip (1.3%)Age x Killip (1.3%)Age x Killip (1.3%)Age x Killip (1.3%) Height (1.1%)Height (1.1%)Height (1.1%)Height (1.1%)

Diabetes (1%)Diabetes (1%)Diabetes (1%)Diabetes (1%)Time-to-Rx (1%)Time-to-Rx (1%)Time-to-Rx (1%)Time-to-Rx (1%)Smoker (0.8%)Smoker (0.8%)Smoker (0.8%)Smoker (0.8%)Weight (0.8%)Weight (0.8%)Weight (0.8%)Weight (0.8%)

Accel t-PA (0.8%)Accel t-PA (0.8%)Accel t-PA (0.8%)Accel t-PA (0.8%)

Prior CABG (0.8%)Prior CABG (0.8%)Prior CABG (0.8%)Prior CABG (0.8%)

HTN (0.6%)HTN (0.6%)HTN (0.6%)HTN (0.6%)

HXHXCV DiseaseCV Disease

(0.4%)(0.4%)

HXHXCV DiseaseCV Disease

(0.4%)(0.4%)

Lee et al. Circulation 1995;91:1659-1668Lee et al. Circulation 1995;91:1659-1668Lee et al. Circulation 1995;91:1659-1668Lee et al. Circulation 1995;91:1659-1668


ECG Classification - GUSTO I OutcomeECG Classification - GUSTO I Outcome

CategoryCategory Occlusion SiteOcclusion Site ECGECG1-Year1-Year

MortalityMortality

1.1. Prox LADProx LAD before septalbefore septal ST VST V1-61-6, I, aVL, I, aVL

25.6%25.6%fasicular or BBBfasicular or BBB

2.2. Mid LADMid LAD before diagonalbefore diagonal ST VST V1-61-6, I, aVL, I, aVL

12.4%12.4%

3.3. Distal LADDistal LAD beyond diagonalbeyond diagonal ST VST V1-41-4 or or

10.2%10.2%DiagonalDiagonal in diagonalin diagonal ST I, aVL, VST I, aVL, V5-65-6

4.4. Moderate-to-Moderate-to- proximal RCAproximal RCA ST II, III, aVF andST II, III, aVF and8.4%8.4%large inferiorlarge inferior or LCXor LCX VV11, V, V33R, VR, V44R orR or

(post, lat, RV)(post, lat, RV) VV5-65-6 or or

R > S VR > S V1-21-2

5.5. Small inferiorSmall inferior distal RCA ordistal RCA or ST II, III, aVF onlyST II, III, aVF only6.7%6.7%

LCX branchLCX branch


Ejection FractionEjection Fraction

Gottlieb et al. Am J Cardiol 1992;69:977-984Gottlieb et al. Am J Cardiol 1992;69:977-984

707030302020 4040 5050 6060

50%50%

40%40%

30%30%

20%20%

00

10%10%

Ejection Fraction (%)Ejection Fraction (%)707030302020 4040 5050 6060

50%50%

40%40%

30%30%

20%20%

00

10%10%

Ejection Fraction (%)Ejection Fraction (%)

Mortality (2-Year)Mortality (2-Year)


Hemodynamic Subgroups - Killip ClassHemodynamic Subgroups - Killip Class

GISSI-1 (%)GISSI-1 (%)

Killip Killip Definition Definition IncidenceIncidence ControlControlLyticLytic

ClassClass MortalityMortalityMortalityMortality

II No CHFNo CHF 7171 7.37.35.95.9

IIII S3 gallop orS3 gallop or 2323 19.919.916.116.1

basilar ralesbasilar rales

IIIIII Pulmonary edemaPulmonary edema 44 39.039.033.033.0

(rales >1/2 up)(rales >1/2 up)

IVIV Cardiogenic shockCardiogenic shock 22 70.170.169.969.9


DiagnosisDiagnosis





Aspirin in Acute MIAspirin in Acute MI

ISIS-2ISIS-2

ISIS-2 Collaborative Group, Lancet 1988;2:349.ISIS-2 Collaborative Group, Lancet 1988;2:349.

PlaceboPlacebo ASAASA SKSK SK + ASASK + ASA00

55

1010

1515

202035 Day Mortality (%)35 Day Mortality (%)

13.213.2

10.710.7 10.410.4

88

43004300 4300430042954295 42924292

Aspirin in Acute MIAspirin in Acute MI

RecommendationsRecommendations

• Indicated in ALL patients with acute MI, Indicated in ALL patients with acute MI, except for true aspirin allergy (not except for true aspirin allergy (not intolerance)intolerance)

• Initiate orally with chewable compound, Initiate orally with chewable compound, at least 160 mg statat least 160 mg stat

some data suggest first dose should some data suggest first dose should be be 650 mg to achieve full antiplatelet 650 mg to achieve full antiplatelet effecteffect

• Continue 325 mg per day indefinitelyContinue 325 mg per day indefinitely

Mahaffey, et al. AJC 77:551–6, 1996Mahaffey, et al. AJC 77:551–6, 1996

Heparin BetterHeparin Better Control BetterControl Better

DeathDeath

t-PAt-PA 17/476 (3.6%)17/476 (3.6%) 20/468 (4.3%) 20/468 (4.3%)

SK/APSACSK/APSAC 28/402 (7.0%) 28/402 (7.0%) 28/389 (7.2%) 28/389 (7.2%)

AspirinAspirin 30/622 (4.8%) 30/622 (4.8%) 29/609 (4.8%) 29/609 (4.8%)

No No AspirinAspirin 15/256 (5.9%) 15/256 (5.9%) 20/248 (8.1%) 20/248 (8.1%)

Any BleedingAny Bleeding

t-PAt-PA 114/476 (23.9%) 114/476 (23.9%) 83/468 (17.7%) 83/468 (17.7%)

SK/APSACSK/APSAC 85/402 (21.1%) 85/402 (21.1%) 56/389 (14.4%) 56/389 (14.4%)

AspirinAspirin 141/622 (22.7%) 141/622 (22.7%) 97/609 (15.9%) 97/609 (15.9%)

No No AspirinAspirin 58/256 (22.7%) 58/256 (22.7%) 42/248 (16.9%) 42/248 (16.9%)

Heparin-Heparin-AllocatedAllocated

Control-Control-AllocatedAllocated Odds Ratio & 95% C.I.Odds Ratio & 95% C.I.

1.51.50.50.5 2.52.51.01.0 2.02.0

0.43

0.36

Heparin for Acute MI?Heparin for Acute MI?

TAMI-3TAMI-3 HARTHART BleichBleich ECSG-6ECSG-6 NHFNHF00

2020

4040

6060

8080

100100

7979 7979 8282

5252

7171

4444

83837575

8080 8080

Heparin No HeparinPatency (%)Patency (%)

T-PA and HeparinT-PA and Heparin

AngioAngio 90 min90 min 18 hrs18 hrs 40 hrs40 hrs 80 hrs80 hrs7 days7 days+ASA+ASA +ASA +ASA +ASA +ASA +ASA+ASA+ASA+ASA

AngioAngio 90 min90 min 18 hrs18 hrs 40 hrs40 hrs 80 hrs80 hrs7 days7 days+ASA+ASA +ASA +ASA +ASA +ASA +ASA+ASA+ASA+ASATopol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.

Acute MIAcute MI

HeparinHeparin

• Intravenous heparin recommended with t-Intravenous heparin recommended with t-PAPA(intial bolus 5000 U, infusion 1000 U/hr, (intial bolus 5000 U, infusion 1000 U/hr, adjust for weight < 50 kg)adjust for weight < 50 kg)

• No clear data for benefit with streptokinase No clear data for benefit with streptokinase and increased bleedingand increased bleeding

• Discontinue after 24 hrs, except for:Discontinue after 24 hrs, except for: atrial fibrillationatrial fibrillation recurrent ischemiarecurrent ischemia anteroapical MI for CVA prophylaxisanteroapical MI for CVA prophylaxis

Acute MIAcute MI

IV HeparinIV Heparin

• Optimal aPTT appears to be 50 to 70 secondsOptimal aPTT appears to be 50 to 70 seconds

• Not indicated with streptokinaseNot indicated with streptokinase

GISSI-2/Int’l and ISIS-3 GISSI-2/Int’l and ISIS-3 SK+ASA=SK+ASA+SQ hepSK+ASA=SK+ASA+SQ hep

GUSTO-IGUSTO-I SK+IV hep = SK+IV hep = SK+SQ hepSK+SQ hep

Risk (at higher levels) of ICBRisk (at higher levels) of ICB

GUSTO-IIGUSTO-II

DeathDeath ReinfarctionReinfarction Arrest (VF)Arrest (VF)00

11

22

33

44


3.64.2

2.83.4

2.22.6

Beta Blocker Placebo

Adjunctive Therapy for Acute MIAdjunctive Therapy for Acute MI

Beta Blockers (Prior to Thrombolytic Era)Pooled Analysis - 7 Day Outcome

Beta Blockers (Prior to Thrombolytic Era)Pooled Analysis - 7 Day Outcome

> 29,000 Patients (26 Trials)> 29,000 Patients (26 Trials)

-13%-13% -20%-20% -15%-15%

Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.47.Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.47.

p<0.02

p<0.02

p<0.05

ReinfarctionReinfarction Recurrent IschemiaRecurrent Ischemia00

1010

2020


2244

1515

2121

Immediate

Delayed

IC HemorrhageIC Hemorrhage00

0.50.5

11

1.51.5


0.280.28

1.41.4

TIMI 2TIMI 2

Immediate vs Deferred MetoprololImmediate vs Deferred Metoprolol

TIMI Study Group. N Engl J Med 1989;320:618.TIMI Study Group. N Engl J Med 1989;320:618.

p<0.02

p<0.01

p<0.03

48% of patients eligible for randomization to beta blocker48% of patients eligible for randomization to beta blocker10% discontinued due to hypotension or bradycardia10% discontinued due to hypotension or bradycardia

48% of patients eligible for randomization to beta blocker48% of patients eligible for randomization to beta blocker10% discontinued due to hypotension or bradycardia10% discontinued due to hypotension or bradycardia

Beta Blockers in Acute MIBeta Blockers in Acute MI

Pooled Analysis of Randomized TrialsPooled Analysis of Randomized Trials

Hennekens et al. NEJM 1996;335:1660.Hennekens et al. NEJM 1996;335:1660.

StudyStudy NN

DuringDuringMIMI

AgentAgent

ISIS-1ISIS-1 16,02716,027AtenololAtenolol

MIAMIMIAMI 5,7785,778MetoprololMetoprolol

TIMI IIBTIMI IIB 1,4341,434MetoprololMetoprolol

NorwegianNorwegian 1,8841,884TimololTimolol

BHATBHAT 3,8373,837PropranololPropranolol

PostPostMIMI

Mortality Odds Ratio & 95% Mortality Odds Ratio & 95% CICI

00 11 22Control BetterControl BetterRxRx Better Better

Beta Blockers in Acute MIBeta Blockers in Acute MI

RecommendationsRecommendations

• IV to oral beta blocker therapy in IV to oral beta blocker therapy in patients without contraindications in patients without contraindications in first 24 hoursfirst 24 hours

• Avoid early therapy in patients with Avoid early therapy in patients with bradycardia, hypotension, inferior MI, bradycardia, hypotension, inferior MI, CHF, impaired LV function, AV block, CHF, impaired LV function, AV block, asthmaasthma

• Continue treatment for at least 2-3 yearsContinue treatment for at least 2-3 years


ACE InhibitorsOutcome in “Megatrials”

ACE InhibitorsOutcome in “Megatrials”

ISIS-4ISIS-4 GISSI-3GISSI-3 ChineseChinese00

55

1010

1515% Mortality (4-6 Weeks)% Mortality (4-6 Weeks)

6.876.87 7.337.336.336.33

7.117.11

9.399.39 9.729.72

ACE-I

Control

Total 85,064 Patients

Mortality Reduction = 5 lives/1000 Rx’d

27,442 27,382 9435 9460 5666 5679

p=0.02 p=0.03

p=0.57


00 11 22

ACE Inhibitors in Acute MIACE Inhibitors in Acute MI


Hennekens et al. NEJM 1996;335:1660.Hennekens et al. NEJM 1996;335:1660.

StudyStudy NN

DuringDuringMIMI

AgentAgent

ISIS-4ISIS-4 58,05058,050CaptoprilCaptopril

GISSI-3GISSI-3 19,39419,394LisinoprilLisinopril

CONSEN IICONSEN II 6,0906,090EnalaprilatEnalaprilat

SAVESAVE 2,2312,231CaptoprilCaptopril

AIREAIRE 2,0062,006RamiprilRamiprilPostPostMIMI

Control BetterControl BetterRxRx Better Better

TRACETRACE 1,7491,749TrandolaprilTrandolapril


MagnesiumMagnesiumMagnesiumMagnesium

MgMg PlaceboPlacebo00

55

1010

1515% Mortality (28 Day)% Mortality (28 Day)

7.807.80

10.2010.20

MgMg PlaceboPlacebo00

55

1010

1515% Mortality (35 Day)% Mortality (35 Day)

7.287.28 6.926.92

LIMIT-2LIMIT-2 ISIS-4ISIS-4

Woods et al.Woods et al.Lancet 1992;339:1553.Lancet 1992;339:1553.

p < 0.05 p = NS

ISIS-4 Collab GroupISIS-4 Collab GroupLancet 1995;345:669.Lancet 1995;345:669.

Magnesium in Acute MIMagnesium in Acute MI

SummarySummary

• Mortality benefit of empiric Rx - conflicting Mortality benefit of empiric Rx - conflicting results results of randomized trialsof randomized trials

possibly due to late administration and possibly due to late administration and low mortality in the ISIS-4 triallow mortality in the ISIS-4 trial

• Correct low serum [MgCorrect low serum [Mg+2+2]]

• Magnesium 1-2 gm bolus over 5 minutes may Magnesium 1-2 gm bolus over 5 minutes may be definitive Rx for Torsade de Pointes or be definitive Rx for Torsade de Pointes or polymorphic ventricular tachycardiapolymorphic ventricular tachycardia


AgentAgent CaCa+2+2AntAnt ControlControlNN

15.0%15.0%NifedipineNifedipine 13.0%13.0% 13581358

Odds Ratio & 95% CIOdds Ratio & 95% CI

00 11 22More MortalityMore MortalityLess MortalityLess Mortality

10.8%10.8%VerapamilVerapamil 13.3%13.3%17751775

13.5%13.5%DiltiazemDiltiazem 13.5%13.5%24662466

12.4%12.4%Verapamil/Verapamil/DiltiazemDiltiazem

13.4%13.4%42414241

13.0%13.0%PooledPooled 13.3%13.3%55995599

Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.52.Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.52.

Calcium Channel AntagonistsCalcium Channel Antagonists


DiagnosisDiagnosis





Extension / IschemiaExtension / Ischemia

Complications of Acute MIComplications of Acute MI

Acute MIAcute MI

ArrhythmiaArrhythmia

Heart FailureHeart Failure

Expansion / AneurysmExpansion / Aneurysm RV InfarctRV Infarct

PericarditisPericarditis

MechanicalMechanical Mural ThrombusMural Thrombus


Intra-Aortic Balloon Pump CounterpulsationIntra-Aortic Balloon Pump Counterpulsation

Decreases systemic afterloadDecreases systemic afterload

Increases diastolic aortic Increases diastolic aortic pressurepressure

Reduces myocardial oxygen demandReduces myocardial oxygen demand

Improves systemic / end-organ Improves systemic / end-organ perfusionperfusion

Variable effects on coronary Variable effects on coronary perfusionperfusion

IABP in Acute MIIABP in Acute MI

IndicationsIndications

Cardiogenic shock not quickly reversed Cardiogenic shock not quickly reversed (indication less firm for hemodynamic (indication less firm for hemodynamic instability without shock)instability without shock)

Acute MR or VSDAcute MR or VSD

Refractory myocardial ischemiaRefractory myocardial ischemia

Refractory ventricular arrhythmiasRefractory ventricular arrhythmias

Useful as a bridge to revascularization and for Useful as a bridge to revascularization and for support during recovery of extensive “stunned support during recovery of extensive “stunned

myocardium”myocardium”


Indications for Invasive Hemodynamic MonitoringRight Heart Catheterization (Swan-Ganz Catheter)

Indications for Invasive Hemodynamic MonitoringRight Heart Catheterization (Swan-Ganz Catheter)

Severe or progressive CHF or pulmonary Severe or progressive CHF or pulmonary edemaedema

VSD or papillary muscle ruptureVSD or papillary muscle rupture

Cardiogenic shock or progressive Cardiogenic shock or progressive hypotensionhypotension

Hypotension unresponsive to fluid RxHypotension unresponsive to fluid Rx

Need for inotropic or IABP supportNeed for inotropic or IABP support

RV infarctionRV infarction

Refractory VTRefractory VT

TamponadeTamponade

Acute MI - Recurrent Infarction / Acute MI - Recurrent Infarction / IschemiaIschemia PathophysiologyPathophysiology

• In distribution of infarct vessel:In distribution of infarct vessel: IRA reperfusion, then reocclusionIRA reperfusion, then reocclusion thrombus propogation, branch occlusionthrombus propogation, branch occlusion distal embolizationdistal embolization reduced coronary perfusion pressure with reduced coronary perfusion pressure with

severe residual IRA stenosissevere residual IRA stenosis reduced collateral flow from stenosed arteryreduced collateral flow from stenosed artery

• At a distance:At a distance: reduced collateral flow from IRAreduced collateral flow from IRA new coronary thrombus (hypercoagulable new coronary thrombus (hypercoagulable

state)state) reduced systemic perfusion pressurereduced systemic perfusion pressure increased myocardial oxygen consumptionincreased myocardial oxygen consumption

Acute MI - ComplicationsAcute MI - Complications

Recurrent Ischemia / InfarctionRecurrent Ischemia / Infarction

• Prevention:Prevention: AspirinAspirin Beta blockersBeta blockers ACE inhibitors with low LVEFACE inhibitors with low LVEF ? heparin with fibrin-specific lytics ? heparin with fibrin-specific lytics

(reocclusion)(reocclusion)

• Treatment:Treatment: Pharmacologic (beta blockers, nitrates)Pharmacologic (beta blockers, nitrates) IABPIABP Urgent revascularizationUrgent revascularization Repeat lytics (antibodies to SK)Repeat lytics (antibodies to SK)

Acute MI - CHF and ShockAcute MI - CHF and Shock

PathophysiologyPathophysiology

• Extensive (or multiple) LV infarction(s) - systolic Extensive (or multiple) LV infarction(s) - systolic dysfunctiondysfunction

• Impaired relaxation, compliance due to infarction or Impaired relaxation, compliance due to infarction or ischemia - diastolic dysfunctionischemia - diastolic dysfunction

• Extensive RV infarction or ischemiaExtensive RV infarction or ischemia

• VSD or acute severe MRVSD or acute severe MR

• Tamponade (w/ or w/o free wall rupture)Tamponade (w/ or w/o free wall rupture)

• OthersOthers

e.g. critical valve stenosis or regurgitation, toxic-e.g. critical valve stenosis or regurgitation, toxic-metabolic, sepsis, beta- or Cametabolic, sepsis, beta- or Ca+2+2-blocker overdose, -blocker overdose, pulmonary embolism, bowel ischemiapulmonary embolism, bowel ischemia

Acute MI - CHF and ShockAcute MI - CHF and Shock

Hemodynamic SubsetsHemodynamic Subsets

SubsetSubset PCWPPCWP CICI Clinical Clinical SettingSetting

(mm Hg)(mm Hg) (l/min)(l/min)

11 < 18< 18 > 2.2> 2.2asymptomaticasymptomatic

22 > 18> 18 > 2.2> 2.2 pulmonary pulmonary congestioncongestion

33 < 18< 18 < 2.2< 2.2 RV failure,RV failure,hypovolemia, hypovolemia,

ororprofound profound

venodilationvenodilation

44 > 18> 18 < 2.2< 2.2 severe LV severe LV dysfxndysfxn

cardiogenic cardiogenic shockshock

Forrester JS et al. NEJM 1976;295:1356 and 1404.Forrester JS et al. NEJM 1976;295:1356 and 1404.

Acute MI - Cardiogenic ShockAcute MI - Cardiogenic Shock

Outcome with PTCAPooled Analysis of 22 Retrospective Studies

Outcome with PTCAPooled Analysis of 22 Retrospective Studies

• Historical Historical control control mortality ~ 80%mortality ~ 80%

• Total 646 ptsTotal 646 pts

• PTCA success PTCA success rate = 76%rate = 76%TotalTotal Successful

PTCASuccessful

PTCAUnsuccessful

PTCAUnsuccessful

PTCA

00

2020

4040

6060

8080

100100Mortality (%)Mortality (%)

4545

3333

8181

Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 461.Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 461.

Acute MI - Mechanical ComplicationsAcute MI - Mechanical Complications

Free Wall RuptureFree Wall Rupture

• Less frequent (1-3.4%), but earlier, with Less frequent (1-3.4%), but earlier, with thrombolysisthrombolysis

• Uncontained Uncontained sudden EMD or asystolesudden EMD or asystole

• Pseudoaneurysm Pseudoaneurysm transient hypotension, transient hypotension, EMD, bradycardia, repetitive emesis, EMD, bradycardia, repetitive emesis, restlessnessrestlessness

• Echocardiogram usually diagnosticEchocardiogram usually diagnostic

• Surgical repair - may require pericardiocentesis Surgical repair - may require pericardiocentesis for uncontained rupturefor uncontained rupture


Interventricular Septal RuptureInterventricular Septal Rupture

• Incidence 1-3% of transmural MIsIncidence 1-3% of transmural MIs

• Acute shock, pulmonary edema, right heart failure, Acute shock, pulmonary edema, right heart failure, new loud pan-systolic murmur (thrill in 50%)new loud pan-systolic murmur (thrill in 50%)

• Diagnose with echocardiogram or ODiagnose with echocardiogram or O22 saturation saturation

step-upstep-up

• Medical stabilization and IABP for CHF, shockMedical stabilization and IABP for CHF, shock

• Early surgical repair for decompensated pts; Early surgical repair for decompensated pts; mortality highest in pts with inferior MI and complex mortality highest in pts with inferior MI and complex ruptures involving RV (~70%), lowest for apical ruptures involving RV (~70%), lowest for apical ruptures (~30%)ruptures (~30%)

• Small asymptomatic VSDs may not require repairSmall asymptomatic VSDs may not require repair


Infarct ExpansionInfarct Expansion

• Potential consequences:Potential consequences: LV aneurysm +/- mural thrombus +/- LV aneurysm +/- mural thrombus +/-

embolizationembolization adverse LV remodeling and CHFadverse LV remodeling and CHF ventricular ruptureventricular rupture ventricular arrhythmiasventricular arrhythmias

• Prevention:Prevention: ACE inhibitorsACE inhibitors ? nitrates? nitrates the “open artery”the “open artery”

Acute MIAcute MI

The “Late Open Artery”The “Late Open Artery”

nn Time toTime to Follow-UpFollow-Up PatentPatentOccludedOccluded

AngioAngio IRAIRAIRAIRA

(days)(days) (months)(months) MortalityMortalityMortalityMortality

CigarroaCigarroa 179179 1-1501-150 4747 0% 0%18%18%

GohikeGohike 102102 < 365< 365 5151 13%13%17%17%

GalvaniGalvani 172172 1010 4343 1% 1%17%17%

WhiteWhite 305305 2828 3939 5%5%10%10%

LamasLamas 946946 44 4242 14%14%24%24%

WeltyWelty 479479 < 90< 90 3434 4% 4%17%17%

Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445.Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445.


Acute Mitral RegurgitationAcute Mitral Regurgitation

• Transient MR common in early MI (20-40%)Transient MR common in early MI (20-40%)

• Associated with advanced age, prior MI, infarct Associated with advanced age, prior MI, infarct extension, recurrent chest pain, CHF, female genderextension, recurrent chest pain, CHF, female gender

• Persistent MR, even mild, associated with increased Persistent MR, even mild, associated with increased long-term mortality post-MIlong-term mortality post-MI

• May be due to papillary muscle or chordal rupture May be due to papillary muscle or chordal rupture or to geometric changes (dilation) of ventricle and or to geometric changes (dilation) of ventricle and annulusannulus

• Most common with inferior MI (single blood supply Most common with inferior MI (single blood supply to posteromedial papillary muscle) - MI often smallto posteromedial papillary muscle) - MI often small

Acute Mitral RegurgitationAcute Mitral Regurgitation

Diagnosis and ManagementDiagnosis and Management

harsh, short systolic murmur - may be muffledharsh, short systolic murmur - may be muffled

sudden CHF +/- hypotension or shock 2-7 days sudden CHF +/- hypotension or shock 2-7 days post MIpost MI

echocardiography (surface or TEE) usually echocardiography (surface or TEE) usually diagnostic - mobile papillary muscle head or flail diagnostic - mobile papillary muscle head or flail MV leafletMV leaflet

LV function often normal or hyperkineticLV function often normal or hyperkinetic

sudden hemodynamic deterioration commonsudden hemodynamic deterioration common

stabilize medically, IABP, then surgical repairstabilize medically, IABP, then surgical repair

surgical mortality high if shock is presentsurgical mortality high if shock is present

role of surgery in MR not due to rupture less role of surgery in MR not due to rupture less clearclear


Right Ventricular InfarctionRight Ventricular Infarction

• Associated with occlusion of proximal RCAAssociated with occlusion of proximal RCA

• Classic triad by hypotension, Classic triad by hypotension, JVP, clear lungs JVP, clear lungs specific but insensitivespecific but insensitive

• Kussmaul’s sign, JVP > 8 cm HKussmaul’s sign, JVP > 8 cm H22O sensitive and O sensitive and

specificspecific

• EKG: STEKG: STin RV4in RV4

• Echo: RV dilation and hypokinesiaEcho: RV dilation and hypokinesia

• PA catheter: RA >10 mm, RA/PCWP ratio PA catheter: RA >10 mm, RA/PCWP ratio >> 0.8 0.8

Acute MI - RV InfarctionAcute MI - RV Infarction

ManagementManagement

• Extensive Extensive irreversibleirreversible infarction is unusual - infarction is unusual - transient ischemic dysfunction with long-term transient ischemic dysfunction with long-term recovery commonrecovery common

• Marked by sensitivity to preload reduction Marked by sensitivity to preload reduction (nitrates, diuretics, morphine), bradycardia, AV (nitrates, diuretics, morphine), bradycardia, AV blockblock

• Fluid volume infusion for hypotension and low Fluid volume infusion for hypotension and low cardiac outputcardiac output

• PCWP elevation may occur due to septal shiftPCWP elevation may occur due to septal shift

• Dobutamine if fluids Dobutamine if fluids RA and RA and PCWP without PCWP without improved BP and CIimproved BP and CI

Acute MI - ArrhythmiasAcute MI - Arrhythmias

Prophylactic LidocaineProphylactic Lidocaine

• Prophylactic use for suppression of VT or VF Prophylactic use for suppression of VT or VF controversialcontroversial

• Overview of randomized trials:Overview of randomized trials: 33% reduction in primary ventricular arrhythmias33% reduction in primary ventricular arrhythmias trend toward 38% increased mortality (asystole)trend toward 38% increased mortality (asystole)

• Potential benefit in reperfusion era - GUSTO I (but not Potential benefit in reperfusion era - GUSTO I (but not a randomized comparison)a randomized comparison)

• Should likely avoid unless VT / VF or non-sustained VT Should likely avoid unless VT / VF or non-sustained VT occursoccurs


0.10.1 11 1010

Acute MI - Antiarrhythmic AgentsAcute MI - Antiarrhythmic Agents


NEJM 1996;335:1660. Lancet 1997;349:667 and 675.NEJM 1996;335:1660. Lancet 1997;349:667 and 675.

StudyStudy NN

ClassClassII

AgentAgent

CASTCAST 1,4981,498Enc / FlecEnc / Flec

CAST IICAST II 1,3251,325MoricizineMoricizine

EMIATEMIAT 1,4861,486AmiodaroneAmiodarone

CAMIATCAMIAT 1,2021,202AmiodaroneAmiodaroneClassClass

IIIIII

Control BetterControl BetterRxRx Better Better

SWORDSWORD 3,1213,121d-Sotalold-Sotalol

Julian et alJulian et al 1,4561,456l-Sotaloll-Sotalol


Ventricular Tachycardia or FibrillationVentricular Tachycardia or Fibrillation

• Prognosis of VT or VF in first 48 hours Prognosis of VT or VF in first 48 hours controversialcontroversial MILIS - no increased in-hospital mortalityMILIS - no increased in-hospital mortality GISSI - increased in-hospital mortalityGISSI - increased in-hospital mortality No increased mortality after hospital No increased mortality after hospital

dischargedischarge

• VT or VF after first 48 hours associated with VT or VF after first 48 hours associated with poorer long-term prognosispoorer long-term prognosis

• Acute management - KAcute management - K++ replacement, replacement, antiarrhythmic therapy (lidocaine, antiarrhythmic therapy (lidocaine, procainamide, or amiodarone) if stable, procainamide, or amiodarone) if stable, electrical shock if unstableelectrical shock if unstable

• Long term management - pharmacologic Long term management - pharmacologic therapy of unclear benefit, ICD may be therapy of unclear benefit, ICD may be beneficialbeneficial


Atrial FibrillationAtrial Fibrillation

• Incidence reduced with thrombolysis (<5%)Incidence reduced with thrombolysis (<5%)

• Associated with large MI (especially if sustained)Associated with large MI (especially if sustained)

• Prognostic of adverse events over following yearPrognostic of adverse events over following year

• Rate control with digoxin, or (without CHF) beta Rate control with digoxin, or (without CHF) beta blockers, verapamil, or diltiazemblockers, verapamil, or diltiazem

• Consider IV amiodaroneConsider IV amiodarone

• Electrical cardioversion for hemodynamic Electrical cardioversion for hemodynamic compromise compromise or ischemiaor ischemia


Indications for Temporary PacingIndications for Temporary Pacing

asystoleasystole

complete (third-degree) AV blockcomplete (third-degree) AV block

second-degree Mobitz II AV blocksecond-degree Mobitz II AV block

second-degree Mobitz I AV block with second-degree Mobitz I AV block with hypotensionhypotension

new bifascicular block, esp with first-degree AV new bifascicular block, esp with first-degree AV blockblock

symptomatic bradycardia, unresponsive to symptomatic bradycardia, unresponsive to atropineatropine

Transcutaneous standby pacing for new LBBB, Transcutaneous standby pacing for new LBBB, sick sinus syndrome with sinus pausessick sinus syndrome with sinus pauses


Indications for Permanent PacingIndications for Permanent Pacing

persistent complete (third-degree) AV blockpersistent complete (third-degree) AV block

persistent sinus node dysfunction - persistent sinus node dysfunction - symptomatic bradycardiasymptomatic bradycardia

intermittent second-degree Mobitz II or third-intermittent second-degree Mobitz II or third-degree AV blockdegree AV block

second-degree Mobitz II or third-degree AV second-degree Mobitz II or third-degree AV block with new bundle branch blockblock with new bundle branch block


DiagnosisDiagnosis





Acute MIAcute MI

Pre-Discharge ManagementPre-Discharge Management

• Risk stratificationRisk stratification

• Catheterization and revascularization Catheterization and revascularization strategystrategy

• Electrophysiologic evaluation for VT or Electrophysiologic evaluation for VT or VFVF

• Lifestyle modification: diet, exercise, Lifestyle modification: diet, exercise, tobaccotobacco

• Pharmacologic therapyPharmacologic therapy


Low RiskLow RiskLow RiskLow Risk High Risk*High Risk*High Risk*High Risk*

LVSFLVSF LVSFLVSF Nl LVSFNl LVSFNl LVSFNl LVSF

Stress ImagingStress Imagingoror

CatheterizationCatheterization

Stress ImagingStress Imagingoror

CatheterizationCatheterization

Nl LVSFNl LVSFNl LVSFNl LVSF LVSFLVSF LVSFLVSF

AngiographyAngiography±±

RevascularizationRevascularization

AngiographyAngiography±±

RevascularizationRevascularization

Stress ImagingStress ImagingStress ImagingStress Imaging

NormalNormalNormalNormal DirectDirectCathCath

DirectDirectCathCath

Post-MI Revascularization StrategyPost-MI Revascularization Strategy

* (Re) MI or CP, VT, CHF, Prior MI, Prior Revascularization* (Re) MI or CP, VT, CHF, Prior MI, Prior Revascularization

Acute MI ManagementAcute MI Management

Pharmacologic Therapy on Hospital DischargePharmacologic Therapy on Hospital Discharge

Aspirin indefinitely (ticlopidine or clopidogrel Aspirin indefinitely (ticlopidine or clopidogrel for aspirin allergy or intolerance)for aspirin allergy or intolerance)

Beta blockers for at least 2-3 yearsBeta blockers for at least 2-3 years

ACE inhibitors for CHF, LVEF<40%, or large ACE inhibitors for CHF, LVEF<40%, or large infarction (even with preserved LVEF)infarction (even with preserved LVEF)

Lipid lowering agentsLipid lowering agents

Coumadin for mural thrombus, extensive Coumadin for mural thrombus, extensive anterior infarct, DVT, atrial fibrillationanterior infarct, DVT, atrial fibrillation

Uncontrolled HTN (BP > 180/110) on Uncontrolled HTN (BP > 180/110) on presentationpresentation

History prior CVA beyond 1 yr History prior CVA beyond 1 yr Anticoagulant Rx with INR > 2-3; bleeding Anticoagulant Rx with INR > 2-3; bleeding

diathesisdiathesis Recent trauma (within 2-4 wks)Recent trauma (within 2-4 wks) Noncompressible vascular puncturesNoncompressible vascular punctures Recent internal bleeding (within 2-4 wks)Recent internal bleeding (within 2-4 wks) PregnancyPregnancy Active peptic ulcerActive peptic ulcer Prior exposure (5 day - 2 yr) for SK or APSACPrior exposure (5 day - 2 yr) for SK or APSAC

Thrombolysis in Acute MIThrombolysis in Acute MI

Relative ContraindicationsRelative Contraindications

Thrombolysis in Acute MIThrombolysis in Acute MI

Absolute ContraindicationsAbsolute Contraindications

Previous hemorrhagic strokePrevious hemorrhagic stroke

CVA within previous yrCVA within previous yr

Intracranial neoplasia or AVMIntracranial neoplasia or AVM

Active internal bleeding (not Active internal bleeding (not menses)menses)

Suspected aortic dissectionSuspected aortic dissection

Myocardial ReperfusionMyocardial Reperfusion

The Original ParadigmThe Original Paradigm

Re-establishRe-establishInfarct VesselInfarct Vessel

PatencyPatency

Re-establishRe-establishInfarct VesselInfarct Vessel

PatencyPatency

Limit InfarctLimit InfarctSizeSize

Limit InfarctLimit InfarctSizeSize MortalityMortality MortalityMortality

Mortality TrialMortality Trial Angiographic TrialAngiographic Trial

41,021 Patients41,021 Patients30-day Outcome30-day Outcome41,021 Patients41,021 Patients

30-day Outcome30-day Outcome2,431 Patients2,431 Patients

TIMI 3 flowTIMI 3 flow2,431 Patients2,431 Patients

TIMI 3 flowTIMI 3 flow

SK+SQHep

SK+SQHep

SK+IVHep

SK+IVHep

Accel.t-PA

Accel.t-PA

t-PA+SK

t-PA+SK

00

1010

2020

3030

4040

5050

6060

29293333

5454

3838

% of Patients% of Patients

SK+SQHep

SK+SQHep

SK+IVHep

SK+IVHep

Accel.t-PA

Accel.t-PA

t-PA+SK

t-PA+SK

00

1010

2020

3030

4040

5050

6060

29293333

5454

3838


SK (IV)SK (SubQ)t-PA + SKAccel. t-PA

88

66

44

22

0000 22 44 66 88 10101212141416161818202022222424262628283030

% Mortality% Mortality

Days from RandomizationDays from Randomization

GUSTOGUSTO

StreptokinaseStreptokinase GISSIGISSI 495/4865495/4865 623/4878623/487823% ± 6

ISAMISAM 50/84250/842 61/86861/86816% ± 18

ISIS-2ISIS-2 471/5350471/5350 648/5360648/536030% ± 5

APSACAPSAC AIMSAIMS 32/50232/502 61/50261/50250% ± 16

t-PAt-PA ASSETASSET 182/2516182/2516 245/2495245/249528% ± 9

Overall: any thrombolyticOverall: any thrombolytic 1230/140751230/14075 1623/141031623/1410327% ± 3 Patients < 6 hoursPatients < 6 hours 8.7%8.7% 11.6%11.6%

OddsOddsAgentAgent Trial NameTrial Name Deaths/Patients Deaths/Patients Odds RatioOdds Ratio

ReductionReductionActiveActive ControlControl (& 95% Cl)(& 95% Cl)

(± s.d.)(± s.d.)

OddsOddsAgentAgent Trial NameTrial Name Deaths/Patients Deaths/Patients Odds RatioOdds Ratio

ReductionReductionActiveActive ControlControl (& 95% Cl)(& 95% Cl)

(± s.d.)(± s.d.)

Lytic betterLytic betterLytic betterLytic better Lytic worseLytic worseLytic worseLytic worse0.00.00.00.0 0.50.50.50.5 1.01.01.01.0 1.51.51.51.5 2.02.02.02.0

Meta-AnalysisMeta-Analysis

Thrombolytic: Placebo-ControlThrombolytic: Placebo-Control

Thrombolysis for Acute MIThrombolysis for Acute MI

00

1010

2020

3030

4040

00 66 1212 1818 2424

Absolute Mortality Reduction per 1000 PatientsAbsolute Mortality Reduction per 1000 Patients

Time from Symptom Onset to Randomization (h)Time from Symptom Onset to Randomization (h)

Time to Therapy and Mortality ReductionPooled Analysis of Randomized Trials

Time to Therapy and Mortality ReductionPooled Analysis of Randomized Trials

Fibrinolytic Therapy Trialists. Lancet 1994;343:311.Fibrinolytic Therapy Trialists. Lancet 1994;343:311.

New FibrinolyticsNew Fibrinolytics

ASSENT IIASSENT IIASSENT IIASSENT II INTIME IIINTIME IIINTIME IIINTIME II

MortalityMortality ICHICH00

11

22

33

44

55

66

77

88

6.156.15 6.176.17

0.940.94 0.930.93

t-PA

TNK

30 Day Outcome (%)30 Day Outcome (%)


11

22

33

44

55

66

77

88

6.156.15 6.176.17

0.940.94 0.930.93

t-PA

TNK



11

22

33

44

55

66

77

88

6.66.6 6.776.77

0.620.621.131.13

t-PA

TNK



11

22

33

44

55

66

77

88

6.66.6 6.776.77

0.620.621.131.13

t-PA

TNK


p=0.003

Thrombolysis for Acute MIThrombolysis for Acute MI

Electrocardiographic Criteria for TherapyPooled Analysis of Randomized Trials

Electrocardiographic Criteria for TherapyPooled Analysis of Randomized Trials

EKGEKG PlaceboPlacebo LysisLysisOdds Ratio & 95% CIOdds Ratio & 95% CI

0.330.33 11 33Placebo BetterPlacebo BetterLysis BetterLysis Better

8.4%8.4%STST Inferior Inferior 7.5%7.5%

13.4%13.4%STST Other Other 10.6%10.6%

13.8%13.8%STST 15.2%15.2%

5.8%5.8%Other AbnormOther Abnorm 5.2%5.2%

2.3%2.3%NormalNormal 3.0%3.0%

16.9%16.9%STST Anterior Anterior 13.2%13.2%

23.6%23.6%BBBBBB 18.7%18.7%

Fibrinolytic Therapy Trialists. Lancet 1994;343:311.Fibrinolytic Therapy Trialists. Lancet 1994;343:311.

Thrombolysis and AgeThrombolysis and Age

<65<65 65-7465-74 75+75+00

1010

2020

3030

4040% Mortality% Mortality

Age (yrs)Age (yrs)

7.77.75.55.5

17.617.615.215.2

28.828.8

24.924.9

Placebo

Streptokinase

26% RR = 1.2%

14% RR = 2.4%

14% RR = 3.9%

GISSI -1 and ISIS -2GISSI -1 and ISIS -2N = 28,896 PatientsN = 28,896 Patients

GUSTO 1GUSTO 1N = 41,021 PatientsN = 41,021 Patients

<=75<=75 >75>7500

1010

2020

3030

4040% Death or Disabling Stroke% Death or Disabling Stroke

Age (yrs)Age (yrs)

6.06.0 5.05.0

21.521.520.220.2

SK

Accel t-PA

17% RR = 1.0%

6% RR =1.3%

PTCA vs Lysis

11 RCTs (2725 patients)11 RCTs (2725 patients) PCAT Collaborative Group, 2001PCAT Collaborative Group, 2001

Acute MIAcute MI

2020

1515

1010

55

0000 22 44 66

Death + MI (%)

p<0.0001

Months from RandomizationMonths from Randomization

Thrombolysis PTCA

Death + MI (%)2020

1515

1010

55

0000 22 44 66

Death + MI (%)

p<0.0001

Months from RandomizationMonths from Randomization

Thrombolysis PTCA

Death + MI (%)

Primary Angioplasty in Acute MIPrimary Angioplasty in Acute MI


TrialTrial PTCAPTCA LysisLysisNN

2.0%2.0%ZijlstraZijlstra 7.4%7.4% 389389

Odds Ratio & 95% CIOdds Ratio & 95% CI

0.10.1 11 1010Lysis BetterLysis BetterPTCAPTCA Better Better

SKSKTrialsTrials

9.3%9.3%GrinfeldGrinfeld 10.3%10.3%112112

6.5%6.5%DeWoodDeWood 4.5%4.5%9090

2.6%2.6%PAMIPAMI 6.5%6.5% 395395

4.3%4.3%GibbonsGibbons 3.6%3.6% 103103

0.0%0.0%RibichiniRibichini 2.4%2.4% 8383

3.2%3.2%ElizagaElizaga 10.6%10.6% 189189

5.7%5.7%GUSTO IIGUSTO II 7.0%7.0%11381138

4.4%4.4%PooledPooled 6.5%6.5% 25992599

6.0%6.0%RibeiroRibeiro 2.0%2.0%100100

t-PAt-PATrialsTrials

AccelAccelt-PAt-PA

TrialsTrials

Topol, Van de Werf. Textbook Cardiovasc Med 1998;p416Topol, Van de Werf. Textbook Cardiovasc Med 1998;p416

Pooled 32% RR

Acute MI: 1995Acute MI: 1995

RESCUERESCUERESCUERESCUE

156 pts < 8 hours chest pain, ant. MI with occluded LAD 156 pts < 8 hours chest pain, ant. MI with occluded LAD

PTCA successful in 92% of patientsPTCA successful in 92% of patients

156 pts < 8 hours chest pain, ant. MI with occluded LAD 156 pts < 8 hours chest pain, ant. MI with occluded LAD

PTCA successful in 92% of patientsPTCA successful in 92% of patients

Outcomes at 30 DaysOutcomes at 30 DaysOutcomes at 30 DaysOutcomes at 30 Days

DeathDeath Severe CHFSevere CHF Death or CHFDeath or CHF00

44

88

1212

1616

2020

9.69.6

5.15.17.07.0

1.31.3

16.616.6

6.46.4

Control

Rescue


DeathDeath Severe CHFSevere CHF Death or CHFDeath or CHF00

44

88

1212

1616

2020

9.69.6

5.15.17.07.0

1.31.3

16.616.6

6.46.4

Control

Rescue


Rest EFRest EF Exercise EFExercise EF00

1010

2020

3030

4040

5050

3939 3838 40404343

%%

Rest EFRest EF Exercise EFExercise EF00

1010

2020

3030

4040

5050

3939 3838 40404343

%%

Pathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMI

*Gibson et al. *Gibson et al. J Am Coll Cardiol.J Am Coll Cardiol. 1995;25:582-589. 1995;25:582-589.Gibson et al. Gibson et al. Circulation.Circulation. 2001;103:2550-2554. 2001;103:2550-2554.

Combination TherapyCombination Therapy

ThrombusThrombus

% Stenosis% Stenosis Minimum DiameterMinimum Diameter

Epicardial FlowEpicardial Flow

Myocardial BlushMyocardial Blush ST ResolutionST Resolution

Myocardial FlowMyocardial FlowFacilitates PCIFacilitates PCI

Reduces Reduces Reinfarction*Reinfarction*

Recent Clinical TrialsRecent Clinical TrialsRecent Clinical TrialsRecent Clinical Trials

Unfractionated heparinEnoxaparinUnfractionated heparinEnoxaparin

AbciximabAbciximab

NoneNone

ENTIRE

ACC/AHA heparin doseLow-dose heparinEnoxaparin

NoneAbciximab

None

ASSENT-3

Standard-dose heparinLow-dose heparin

NoneAbciximab

50% TNK-tPA50% TNK-tPA100% TNK-tPA100% TNK-tPA

100% TNK-tPA50% TNK-tPA100% TNK-tPA

100% r-PA50% r-PA

GUSTO-V

AnticoagulantGP IIb/IIIa

Receptor InhibitorLyticTrial

Clinical Trials: OngoingClinical Trials: OngoingClinical Trials: OngoingClinical Trials: Ongoing

Low-dose heparinLow-dose heparinLow-dose heparin

EptifibatideEptifibatideEptifibatide


INTEGRITI

Low-dose heparinLow-dose heparinLow-dose heparin

TirofibanTirofibanTirofiban


FASTER

AnticoagulantGP IIb/IIIa

Receptor InhibitorLyticTrial

54%54%

32%32%

GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality ReductionNeeded to Yield a 1% Mortality ReductionGUSTO-I: A 20% Increase in TIMI Grade 3 Flow is GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality ReductionNeeded to Yield a 1% Mortality Reduction

The GUSTO Angiographic Investigators. The GUSTO Angiographic Investigators. N Engl J Med.N Engl J Med. 1993;329:1615-1622. 1993;329:1615-1622.

0

30

50

60

40

20

% T

IMI

Gra

de

3 F

low

t-PA SK

10

t-PA

5

7.4%7.4%

6.3%6.3%

SK

876

TIMI Grade 3 Flow – Pooled Data From Dose TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent TrialsConfirmation Phases of Recent TrialsTIMI Grade 3 Flow – Pooled Data From Dose TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent TrialsConfirmation Phases of Recent Trials

0

40

80

100

60

20

% P

atie

nts

Wit

h T

IMI

Gra

de

3 F

low

GUSTO-I90 min

T14 t-PA90 min

T14 r-PA90 min

SPEED60-90 min

INTRO-AMI60 min

Pooled60-90 min

54

7370

47

40

56

7873

54 56

64

292292 6363 8787 9898 8181 3293295858 8888 100100 7575 321321

Lytic alone

Combination

SPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation Phase

• There was a 7.4% improvement in the rate of TIMI Grade 3 flow

• If a 20% improvement is required to improve mortality by 1%, then a 7.4% improvement would be predicted to improve mortality by 0.3%

The SPEED Study Group. The SPEED Study Group. Circulation.Circulation. 2000;101:2788-2794. 2000;101:2788-2794.

0

40

80

100

r-PA 10+10 U r-PA 5+5 U + Abx

60

20

Pat

ency

(%

)

TIMI-2

TIMI-3

n=109n=109 n=115n=115

21.621.6

54.954.947.547.5

28.728.7

GUSTO-V: Study DesignGUSTO-V: Study DesignGUSTO-V: Study DesignGUSTO-V: Study Design

The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.

ST , lytic eligible, < 6 h (n=16,588)

ASA

No AbciximabNo Abciximab

2 x 10 U bolus (30’)

Full-dose r-PA

2 x 10 U bolus (30’)

Full-dose r-PA

Abciximab Abciximab

Low-dose Heparin:60 U/kg bolus followed by

7 U/kg/h infusion

Low-dose Heparin:60 U/kg bolus followed by

7 U/kg/h infusion

1º end point: mortality at 30 days2º end point: clinical and safety events at 30 days

2 x 5 U bolus (30’)

Half-dose r-PA

2 x 5 U bolus (30’)

Half-dose r-PA

Standard Heparin: 5000 U bolus followed by

800 U/h (< 80 kg) or 1000 U/h ( 80 kg) infusion

Standard Heparin: 5000 U bolus followed by

800 U/h (< 80 kg) or 1000 U/h ( 80 kg) infusion

Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality


0

% M

ort

alit

y

Days0 5 10 15 20 25 30

P=.43 for superiority

Non-Inferiority RR 0.95(95% CI, 0.84-1.08)

Std. Reteplase (n = 8260)Abx + Dose Reteplase (n = 8328)

4

6

2

5.9%

5.6%

GUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority Analysis

Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:1905-1914.

Non-Inferiority RR 0.95(95% CI, 0.84-1.08)

1.111.11

OR and 95% CI

0.00.0 2.02.01.01.0Abciximab + Abciximab + Half-dose r-PA superiorHalf-dose r-PA superior

Full-dose r-PAFull-dose r-PAsuperiorsuperior

Upper Boundary of 95% CI for NoninferiorityUpper Boundary of 95% CI for Noninferiority

A Comparison of the Outcomes With r-PA A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V TrialsMonotherapy in GUSTO-III vs GUSTO-V TrialsA Comparison of the Outcomes With r-PA A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V TrialsMonotherapy in GUSTO-III vs GUSTO-V Trials

The GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.


0

3

7

8

5

1

2

6

4

GUSTO III GUSTO V

7.4%

5.9%

10,13810,138 8,2608,260

Death

P<.001

0

40

50

20

30

10

GUSTO III GUSTO V

48%

37%

10,13810,138 8,2608,260

Anterior MI

0

0.5

0.9

1.0

0.7

0.3

0.4

0.8

0.6

0.2

GUSTO III GUSTO V

0.91%

0.59%

10,13810,138 8,2608,260

ICH

P=.015

0.1

0.2

1.2

1.7

2.3

GUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of Reinfarction

*Unblinded, unadjudicated


0

1

3

4

2

Myo

card

ial

Infa

rcti

on

(%

)

Any Q-wave Enzymatic Ischemic STChange*

3.5

0.5

1.6

2.7

r-PA

r-PA + Abx

P<.0001

Non-Intracranial Bleeding Through Non-Intracranial Bleeding Through Discharge/Day 7Discharge/Day 7Non-Intracranial Bleeding Through Non-Intracranial Bleeding Through Discharge/Day 7Discharge/Day 7


0

% o

f P

atie

nts

15

25

30

20

r-PA

r-PA + Abx

10

SevereBleeding

ModerateBleeding

MildBleeding

AnyBleeding

ReceivingTransfusions

10

0.5 1.1 1.83.5

11.4

20.0

13.7

24.6

4.05.7

ICH by Age GroupICH by Age GroupICH by Age GroupICH by Age Group

*Significant treatment interaction for the age 75 dichotomy; P=.033.


0

1

3

2

% o

f P

atie

nts

70 yrs > 70 yrs 75 yrs > 75 yrs

0.4

1.2

0.5

1.1

1.5

0.4

2.1

r-PA (n=8260)

r-PA + Abx (n=8328)

0.3

P=.66

P=.53

P=.27*

P=.069*

12/108812/1088 24/114924/114928/717928/717937/717237/717225/203025/2030 31/213531/213521/619321/619324/623024/6230

**

****

**

GUSTO-V: PCI Within 6 Hours (Urgent) GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7and Through Day 7GUSTO-V: PCI Within 6 Hours (Urgent) GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7and Through Day 7

*P<.0001.


5.65.6

25.425.427.927.9

8.68.6

0

15

25

30

20

10

PC

I (%

)

Urgent

Through Day 7

5

r-PA r-PA + Abx

2.8

9.0

5.4

GUSTO-V: Event Rates in Those Requiring GUSTO-V: Event Rates in Those Requiring Urgent PCIUrgent PCIGUSTO-V: Event Rates in Those Requiring GUSTO-V: Event Rates in Those Requiring Urgent PCIUrgent PCI

Heartwire News. September 2, 2001. GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?

6.7

4.8

9.6

0

4

10

12

8

Myo

card

ial

Infa

rcti

on

(%

)

r-PA

r-PA + Abx

n=1173

Death Repeat MI Death Plus Repeat MI

2

6

GUSTO-V: ConclusionsGUSTO-V: ConclusionsGUSTO-V: ConclusionsGUSTO-V: Conclusions

• Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in

– A mortality rate that was not inferior to r-PA monotherapy

– Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation)

– A lower rate of urgent revascularization

– More noncerebral bleeding complications, transfusions, and thrombocytopenia

– A higher rate of ICH in elderly patients over the age of 75 years

ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin

• TNK-tPA plus enoxaparin

– Favorable effects of LMWHs in recent small-scale thrombolysis trials

– Higher late patency: HART-2ASSENT-PlusAMI-SK

– Less reocclusion: HART-2

– Fewer reinfarctions: ASSENT-PlusAMI-SKWilson, et al.

• ASSENT-3 is the first large-scale trial to test LMWH

ASSENT-3: Study DesignASSENT-3: Study DesignASSENT-3: Study DesignASSENT-3: Study Design

ST-Segment Elevation AMI (n=6095 patients)ST-Segment Elevation AMI (n=6095 patients)

150 to 325 mg ASA (daily)150 to 325 mg ASA (daily)

RandomizedRandomized

Full-dose TNK-tPAPlus Enoxaparin

Full-dose TNK-tPAPlus Enoxaparin

Half-dose TNK-tPAPlus Abciximab

Plus Low-dose Heparin

Half-dose TNK-tPAPlus Abciximab

Plus Low-dose Heparin

Full-dose TNK-tPAPlus Weight-adjusted UFH

Full-dose TNK-tPAPlus Weight-adjusted UFH

The ASSENT-3 Investigators. Lancet. 2001;358:605-613.

ASSENT-3: Primary End PointsASSENT-3: Primary End PointsASSENT-3: Primary End PointsASSENT-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.

ASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory IschemiaRefractory IschemiaASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory IschemiaRefractory Ischemia

0

5

10

15

20

% R

isk

of

30-D

ay D

/MI/

Ref

Isc

h

TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

*P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0002 for the enox vs UFH comparison, and P<.0001 for the abx vs UFH comparison.

11.4 11.1

15.4

3-way P=.0001

P=.0002*P=.0009*

ASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICHRefractory Ischemia, Major Bleeding and ICHASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICHRefractory Ischemia, Major Bleeding and ICH

% R

isk

of

30-D

ay D

/MI/

Ref

Isc

h/M

aj B

leed

/IC

H

*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.

0

5

10

15

20


13.8 14.2

17.0

3-way P=.0062

P=.0057*P=.0146*

Kaplan-Meier Curves Kaplan-Meier Curves Kaplan-Meier Curves Kaplan-Meier Curves

UFH

Abx*

5 10 15 20 25 30

0

2

4

6

8

10

12

14

16

20

18

0

Enox*

log-rank P=.0001*vs UFH

Days to death, reinfarction, orrefractory ischemia

Primary Efficacy End Point

Pro

bab

ility

(%

)

Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:605-613.

5 10 15 20 25 30

0

2

4

6

8

10

12

14

16

20

18

0

log-rank P=.0062*vs UFH + Abx

Days to death, reinfarction, refractoryischemia, ICH, or major bleeding

Primary Efficacy PlusSafety End Point

Pro

bab

ility

(%

)

UFH

Abx

Enox*

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of AgeMajor Bleeding in Patients >75 Years of Age

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of AgeMajor Bleeding in Patients >75 Years of Age

*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).

% R

isk

of

30-D

ay E

ffic

acy

and

Saf

ety

En

d P

oin

t

0

15

25

35

45


25.5

36.9

28.0

P=.001*

5

20

30

40

10

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with DiabetesMajor Bleeding in Patients with Diabetes

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with DiabetesMajor Bleeding in Patients with Diabetes

*There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007).

% R

isk

of

30-D

ay E

ffic

acy

and

Saf

ety

En

d P

oin

t

0

15

25

30


13.9

22.3

16.5

P=.007*

5

20

10

ASSENT-3: 30-Day MortalityASSENT-3: 30-Day MortalityASSENT-3: 30-Day MortalityASSENT-3: 30-Day Mortality

0

4

8

10


5.4

6.66.0

3-way P=.25

6

2

% R

isk

of

30-D

ay M

ort

alit

y

ASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MI%

Ris

k o

f 30

-Day

Dea

th o

r M

I

0

4

8

10


6.87.3

9.13-way P=.0198

6

2

ASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MI%

Ris

k o

f In

-Ho

spit

alR

ecu

rren

t M

I

0

2

4

5


2.7

2.2

4.2

3-way P=.0009

3

1

ASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory Ischemia%

Ris

k o

f 30

-Day

Ref

ract

ory

Isc

hem

ia

0

4

8

10


4.6

3.2

6.5

3-way P<.0001

6

2

ASSENT-3: Incidence of In-Hospital ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Thrombocytopenia and Noncerebral Bleeding ComplicationsComplications

ASSENT-3: Incidence of In-Hospital ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Thrombocytopenia and Noncerebral Bleeding ComplicationsComplications

*While 3-way P-value is significant, Enox vs UFH comparison P=NS

Enox Abx UFH P-Value(n=2040) (n=2017) (n=2038) 3-way

Any thrombocytopenia 1.2 3.2 1.3 <.0001

Thrombocytopenia <.0001<20,000 cells/µL 0.1 0.5 0.220,000 to 50,000 cells/µL 0.2 0.6 0.250,000 to <100,000 cells/µL 0.9 2.0 1.0

Bleeding episodesTotal 25.6* 39.7 21.1 <.0001Major 3.0* 4.3 2.2 .0005Minor 22.6* 35.4 18.8 <.0001

Blood transfusion 3.4* 4.2 2.3 .0032

ASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke Rates

*Including hemorrhagic conversion

Unclassified

Hemorrhagic conversion

Ischemic stroke*

Intracranial hemorrhage

Total strokes

0.150.15

0.070.07

0.400.64

0.940.88

1.491.62

Abx(n=2017)

Enox(n=2040)

0.590.05

0.770.00

0.570.54

0.980.93

0.941.52

P-ValueUFH

(n=2038)

Patients Undergoing PCI: MortalityPatients Undergoing PCI: MortalityPatients Undergoing PCI: MortalityPatients Undergoing PCI: Mortality

ASSENT-3: In-Hospital PCI GUSTO-V: Urgent PCI

0

5

7

8

6

3

Mo

rtal

ity

(%)

4

2

1

2.5

3.7

2.7

5.4

6.7

TNK-tPA +Enox

TNK-tPA +Abx

TNK-tPA +UFH

r-PA +UFH

r-PA +Abx

How Does Actual Weight Compare to How Does Actual Weight Compare to Estimated Weight?Estimated Weight?How Does Actual Weight Compare to How Does Actual Weight Compare to Estimated Weight?Estimated Weight?

Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

Correlation Between Estimated and Actual Patient Weight in TIMI 10BCorrelation Between Estimated and Actual Patient Weight in TIMI 10B

40.5

36.4

188.5

Act

ual

Pat

ien

t W

eig

ht

(kg

)

Estimated Patient Weight (kg)

R2=0.93, P<.0001

181

Weight-Based Dosing of Thrombolysis: How Well Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Translate Into Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? Thrombolytic Drugs and Adverse Outcomes?

Weight-Based Dosing of Thrombolysis: How Well Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Translate Into Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? Thrombolytic Drugs and Adverse Outcomes?

1. 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).

2. 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.

Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

ASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding

TNK-tPA + Abciximab TherapyTNK-tPA + Abciximab Therapy

ASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding

TNK-tPA + Abciximab TherapyTNK-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.”


ASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding EnoxaparinEnoxaparinASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding EnoxaparinEnoxaparin

“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.”


ENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study Design

ST MI <6h (n=461)ST MI <6h (n=461)

UFH60 U/kg bolus

12 U/kg/h infusion 36 h

UFH60 U/kg bolus


ENOXvarying doses

+/- IV bolusIndex Hosp ( 8

d)

ENOXvarying doses


d)

ASAASA

ENOXvarying doses


d)

ENOXvarying doses


d)

Combination Reperfusion:

Half-dose TNK-tPA + Abx(0.27 mg/kg)

Combination Reperfusion:

Half-dose TNK-tPA + Abx(0.27 mg/kg)

Standard Reperfusion:

Full-dose TNK-tPA(0.53 mg/kg)

Standard Reperfusion:

Full-dose TNK-tPA(0.53 mg/kg)

Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.

UFH 40 U/kg bolus


UFH 40 U/kg bolus


Outstanding IssuesOutstanding IssuesOutstanding IssuesOutstanding Issues

• Should enoxaparin replace UFH as the optimal antithrombin agent for AMI?

• Will similar improvements in efficacy and safety occur if enoxaparin is combined with a less fibrin-specific agent such as r-PA?

• Will physicians accept the use of enoxaparin in selected patients with ST-elevation MI who may require rescue PCI?

• Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce results similar to ASSENT-3?

• What is the optimal strategy for facilitated PCI?

Future Trials: Potential Downstream TargetsFuture Trials: Potential Downstream TargetsFuture Trials: Potential Downstream TargetsFuture Trials: Potential Downstream Targets

• Large embolii: Filters

• Small embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitors

• Vasoconstrictor release: GP IIb/IIIa inhibitors

• Spasm: Adenosine, Ca channel blockers, alpha blockers, avoid over sizing with PCI, high pressure inflations, serotonin inhibitors, endothelin inhibitors

• Endothelial & Myocardial swelling: Myocardial cooling, Ca channel blockers, DHEA, Na / H pump inhibitors, anti-inflammatory approaches

Conclusions (cont.)Conclusions (cont.)Conclusions (cont.)Conclusions (cont.)

Antiplatelet Agents — ASA & GP IIb/IIIa Blockers

• ASA in treating ACS reduces relative risks of CVD/MI by 35%-50%

• GP IIb/IIIa blockers offer benefits in…

– CVD/MI/emergency revascularization: RRR up to 50%

– CVD/MI: RRR 10% to 27%

• Patients undergoing PTCA also have benefited from GP IIb/IIIa inhibitors

• Patients with acute MI may benefit from GP IIb/IIIa inhibition + thrombolysis


Anticoagulants — Indirect Antithrombins —

UFH & LMWH

• Antithrombin therapy treats acute exacerbation via short-term treatment

• UFH+ASA better than placebo or ASA alone in reducing CVD/MI/RA

• LMWH has clinical advantages over UFH, and is a useful agent early in treatment


Anticoagulants — Direct Antithrombin - Hirudin• Studied internationally in 29,000+ patients• Neutralizes clot-bound and soluble fibrin; no allergic

reactions (lack of HIT)• In acute MI, hirudin and UFH have equivalent effects

as adjunctive therapy to thrombolysis• In PTCA, hirudin is associated with fewer cardiac

events compared to UFH• In ACS, hirudin is superior to UFH:

– CVD/MI RRR 14% — 24%– CVD/MI/RA RRR 19% — 22%


Summary

• Direct thrombin inhibition offers benefits over indirect thrombin inhibition for ACS

• Hirudin appears to be a safe, superior alternative to UFH

• Longer treatment durations need to be assessed for possible long-term benefits

• Combining a thrombin-specific inhibitor (eg, hirudin) with a GP IIb/IIIa blocker may be an even more effective antithrombotic therapy for ACS

Comparative Advantages of Comparative Advantages of Stress Echocardiography and Stress Radionuclide Perfusion Imaging in Stress Echocardiography and Stress Radionuclide Perfusion Imaging in Diagnosis of CADDiagnosis of CAD

Comparative Advantages of Comparative Advantages of Stress Echocardiography and Stress Radionuclide Perfusion Imaging in Stress Echocardiography and Stress Radionuclide Perfusion Imaging in Diagnosis of CADDiagnosis of CAD

• Advantages of Stress Echocardiography

1. Higher specificity

2. Versatility - more extensive evaluation of cardiac anatomy and function

3. Greater convenience / efficacy / availability

4. Lower cost

• Advantages of Stress Perfusion Imaging

1. Higher technical success rate

2. Higher sensitivity - especially for single vessel coronary disease involving the left circumflex

3. Better accuracy in evaluating possible ischemia when multiple resting LV wall motion abnormalities are present

4. More extensive published data base - especially in evaluation of prognosis

Prognostic Markers in Exercise TestingPrognostic Markers in Exercise Testing The Duke Treadmill Score (risk calculation)The Duke Treadmill Score (risk calculation)Prognostic Markers in Exercise TestingPrognostic Markers in Exercise Testing The Duke Treadmill Score (risk calculation)The Duke Treadmill Score (risk calculation)

The Duke treadmill score =

– exercise time in minutes on Bruce Protocol

– minus 5x the ST-segment deviation(during or after exercise, in millimeters)

– 4x the angina index(“0” if there is no angina, “1” if angina occurs, and "2" if angina is the reason for stopping the test).

• works well for both inpatients and outpatients, and equally well for men and women

N Engl J Med 1991;325:849-53

Survival According to Risk Groups Based on Duke Treadmill ScoreSurvival According to Risk Groups Based on Duke Treadmill ScoreSurvival According to Risk Groups Based on Duke Treadmill ScoreSurvival According to Risk Groups Based on Duke Treadmill Score

4 -Year Annual

Risk Group (Score) Total Survival Mortality

Low ( +5) 62% 99% 0.25%

Moderate (-10 to +4) 34% 95% 1.25%

High (< -10) 4% 79%5.00%

N Engl J Med 1991;325:849-53

Risk Stratification With Coronary AngiographyRisk Stratification With Coronary AngiographyRisk Stratification With Coronary AngiographyRisk Stratification With Coronary Angiography

• the extent and severity of coronary disease and LV dysfunction are the most powerful clinical predictors of long-term outcome

– proximal coronary stenoses

– severe left main coronary artery stenosis

• CASS registry of medically treated patients, the 12-year survival rate

Coronary arteries Ejection fraction

normal coronary arteries 91% 50% to 100% 73%one-vessel disease 74% 35% to 49%54%two-vessel disease 59% <35% 21%three-vessel disease 40%

Circulation 1994;90:2645-57

Risk Factors for Risk Factors for Coronary Artery DiseaseCoronary Artery DiseaseRisk Factors for Risk Factors for Coronary Artery DiseaseCoronary Artery Disease

• Age: > 45 y/o male; > 55 y/o female; or post-menopausal female without estrogen therapy

• Male gender

• Hypertension

• Diabetes mellitus

• Hypercholesterolemia/Hypertriglyceridemia

• Smoking

• Family history of early CAD

female age < 65; male age < 55

• Past personal history of PVD or CVA

Risk Factors for Risk Factors for Coronary Artery Disease (con’t)Coronary Artery Disease (con’t)Risk Factors for Risk Factors for Coronary Artery Disease (con’t)Coronary Artery Disease (con’t)

• Left ventricular Hypertrophy

• Cocaine/Ethanol Abuse

• Obesity

• Sedentary Lifestyle

• Oral contraceptives

• Homocysteine elevation

• Fibrinogen, C-reactive protein, Lp (a)

Guidelines to Reduce Risk For Patients With Guidelines to Reduce Risk For Patients With Coronary Disease and other vascular diseaseCoronary Disease and other vascular disease

Cessation of smokingCessation of smoking Lipid Management GoalsLipid Management Goals Primary Goal: LDL < 100 mg/dl Primary Goal: LDL < 100 mg/dl Secondary: HDL > 35 mg/dl TG < 150 mg/dl Secondary: HDL > 35 mg/dl TG < 150 mg/dl Physical activity: 30 minutes 3-4 times per weekPhysical activity: 30 minutes 3-4 times per week Weight managementWeight management Antiplatelet/anticoagulants:ASA 80 to 325 mg/day Antiplatelet/anticoagulants:ASA 80 to 325 mg/day (or clopidogrel 75m/day)(or clopidogrel 75m/day) ACE inhibitors (post-MI for LVD)ACE inhibitors (post-MI for LVD) Beta blockers for high-risk patients post-MI Beta blockers for high-risk patients post-MI Blood pressure control: goal Blood pressure control: goal << 130/85 mm Hg 130/85 mm Hg

Adapted from Smith, Circulation 1995;92:3Adapted from Smith, Circulation 1995;92:3

Medical Therapy For Patients Medical Therapy For Patients with CAD or Other Vascular Diseasewith CAD or Other Vascular Disease

Adapted from the UCLA CHAMP Guidelines 1994Adapted from the UCLA CHAMP Guidelines 1994

Risk Reduction

• ASA 20-30%

• Beta Blockers 20-35%

• ACE inhibitors 22-25%

• Statins 25-42%

The four medications every atherosclerosis patient should be treated with, unless contraindications exist and are documented

IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockers

Randomize

Angio 18-36 hrs

t-PA0.8 mg/kg over 90 mins

391 Patients with Unstable Angina / NQWMI391 Patients with Unstable Angina / NQWMI

Placebo

Primary Endpoint:Death, MI,Positive ETT 6 weeks Follow-up 6 weeks Circulation 1993;87:38-52

Baseline AngioAngio Exclusion: no CAD or LMain

TIMI IIIATIMI IIIA Protocol Design

Apparent thrombus35%

Possible thrombus30%

No thrombus35%

Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NS

TIMI IIIA Investigators. Circulation 1993;87:38-52.

TIMI IIIATIMI IIIAEffects of tPA on Coronary Lesions

Primary Results

BASELINE ANGIORAPHY:

ANGIORAPHY AFTER tPA:

ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockers

Randomize

ETT 6 weeks

Early Invasive:Cath 18-48 h

PTCA/CABG prn

1473 Patients with Unstable Angina / NQWMI1473 Patients with Unstable Angina / NQWMI

Early Conservative:

ST Holter, ETT Thallium

Cath/PTCA if +ischemia1o Endpoint Inv-Cons:

Death, MI,Positive ETT - 6 weeks

Follow-up 1 yearCirculation 1994;89:1545-56

2x2 Factorial:2x2 Factorial:t-PA vs. Placebot-PA vs. Placebo

1o Endpoint t-PA:Death, MI, Rec Isch,+ ETT, Thallium or ST Holter

TIMI IIIBTIMI IIIB Protocol Design

TIMI IIIB Investigators. Circulation 1994;89:1545-56

TIMI IIIBTIMI IIIB

tPA vs. Placebo in Non-ST Elevation ACSPrimary Results

54.2 55.5

0

10

20

30

40

50

60

70

80

tPA Placebo

8.8

6.2

0

2

4

6

8

10

12

tPA Placebo

0.55

00

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

tPA Placebo

Composite Endpoint Death or MI ICH

% o

f P

atie

nts

P = NS P = 0.05 P = 0.05

TIMI IIIB Investigators. Circulation 1994;89:1545-56

TIMI IIIBTIMI IIIB

Early Invasive vs. Conservative Strategy

Primary Results

Events at 42dEvents at 42d InvasiveInvasive ConservativeConservative pp valuevalueNo. Pts 740 733Death (%) 2.4 2.5 NSMI (%) 5.1 5.7 NSD/MI/+ETT (%) 16.2 18.1 NS

Rehosp Angina (%) 7.8 14.1 <0.001D/MI/Rehosp (%) 15 22 0.007LOS (days) 10.2 10.9 <0.001# Days rehosp 365 930 <0.001

• All consecutive patients admitted with unstable angina were screened.

• Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI

• Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure

• Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year.

TIMI IIITIMI III RREGISTRYEGISTRY Protocol Design

2.6 3.6

11

0.8

6.6

22.9

1.63.7

6.8

1.63.7

8.2

In-Hospital 6 Weeks 1 Year0

5

10

15

20

25

% o

f P

ati e

nts

ST deviation >0.1 mV LBBB Tw change No ECG changes_

Stone PH, TIMI III Registry Study Group. JAMA 1996;275:1104-1112.Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:133-40.

TIMI IIITIMI III RREGISTRYEGISTRY

Admission ECG as a prognostic indicator

Risk Stratification

Death or MI

Antman et al. NEJM 1996; 335:1342-9

0 1 2 3 4 5

No CKMB Elev

All Patients

No CKMB Elev

All Patients

No CKMB Elev

All Patients

Mortality at 42 Days (%)

TnI < 0.4 ng/mlTnI > 0.4 ng/ml

Enrolled 0-6 hrs

Enrolled 6-24 hrs

Enrolled 0-24 hrs

P<0.001

P <0.05

P <0.05

P<0.001

TIMI IIIBTIMI IIIBcTnI to Predict Risk of Mortality in ACS

Risk Stratification

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