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
palmsprings@eth.net
Dr.Sarma@works
Ischemic Heart Disease
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 Franklin
13 November 1789 (letter)
Lysis or Life-flight ?
Comorbidity of Atherosclerotic Disease
a major health burden
• Atherothrombosis
• major complications of
atherosclerosis are
thrombosis, with local
occlusion or distal
embolization
CAD
CVA
PAD
Aronow WS, Ahn C. Am J Cardiol. 1994;74:64–65.
Atherosclerosis Time-line
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion/
Rupture
Endothelial Dysfunction
From First
Decade
From Third
Decade
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).
From Fourth
Decade
Left Coronary Artery
Right 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
Dr.Sarma@works
Clinical Assessment
The 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)
Dr.Sarma@works
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
Dr.Sarma@works
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)
Dr.Sarma@works
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 pain
meets  1 of the typical angina characteristics
Dr.Sarma@works
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
Dr.Sarma@works
Chest Pain Checklist
YES
•
•
•
•
•
•
•
•
•
NO
•
•
•
•
•
•
•
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
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
2. Arrival time
3. Begin transport
4. Hospital arrival
____ AM/PM
____ AM/PM
____ AM/PM
____ 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
Dr.Sarma@works
Acute Coronary Syndrome
Ischemic Discomfort
Unstable Symptoms
No ST-segment
elevation
Unstable
Angina
History
Physical Exam
ST-segment
elevation
NSTEMI
(Non-Q MI)
STEMI
(Q-wave MI)
(positive cardiac biomarker)
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ECG
(10 min)
Cardiac
Biomarkers
ACC/AHA Classifications
Expert Opinion and Recommendations
I IIa IIb III
Intervention is useful and effective
Evidence conflicts/opinions differ but
leans towards efficacy
Evidence conflicts/opinions differ but
leans against efficacy
Intervention is not useful/effective
and may be harmful
Dr.Sarma@works
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
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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
Dr.Sarma@works
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 thirddegree atrioventricular block, atrial fibrillation or ventricular
tachyarrhythmias
Dr.Sarma@works
Am J Cardiol 1982;49:1604-14
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
Dr.Sarma@works
– left atrial enlargement
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
Dr.Sarma@works
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
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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
Dr.Sarma@works
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.
Dr.Sarma@works
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
Dr.Sarma@works
Myocardial Markers
MARKER
1st SEEN REL.  DURATION SENS.
(median) (x Nl)
(hrs)
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?
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Size of Myocardial
Infarction (grams)
100
10
1
0.1
0.01
0.001
EKG
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ECHO CK, CK- TROPONIN
AST MB
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
Dr.Sarma@works
The Progressive Development of
Cardiovascular Disease
Risk Factors
Endothelial Dysfunction
Atherosclerosis
CAD
Myocardial Ischemia
Coronary Thrombosis
Myocardial Infarction
Arrhythmia & Loss of Muscle
Remodeling
Ventricular Dilation
Congestive Heart Failure
Dr.Sarma@works
Endstage Heart Disease
Atherosclerosis: the Pathologic Process
Atherosclerotic
Plaque
Plaque
Fissure/
Cracking/
Rupture
Thrombus
Formation
Stabilized
Plaque
Chronic Ischemia
Dr.Sarma@works
Thrombus
Incorporated
into Atheroma
Embolism
Occlusion
Acute Event
Cardiac Enzyme bio-markers
RELATIVECONCENTRATION
M
y
o
g
l
o
b
i
n
T
r
o
p
o
n
i
n
C
K
,A
S
T
L
D
H
N
o
r
m
a
l
0
6
1
2
1
8
2
4
2
3
4
5
6
7
8
9
1
0
H
o
u
r
s
D
a
y
s
T
I
M
E
A
F
T
E
R
I
N
F
A
R
C
T
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MYOFIBER
STRUCTURE
TnI
TnC
Actin
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TnT
Tropomyosin
Inferior MI changes fully evolved
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Posterior MI
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ST ↓ - Ischemia Lateral wall
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ST segment ↑– Acute evolving MI
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ST segment ↑– Inferio-lateral MI
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Evolution of Acute MI
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Acute MI Anterior wall
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Anterio-septal MI with RBBB
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Extensive Anterio-lateral MI
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Fully Evolved MI Anterioseptal
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MI inferio-posterior
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Inferio-posterior MI with RV MI
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Risk Factors for Atherosclerotic
Disease
Non-modifiable



Age
Family history
Sex
Modifiable






Dr.Sarma@works
Cigarette
smoking
Diabetes
mellitus
Hyperlipidemia
Hypertension
Obesity
Physical
inactivity
Hoeg JM. JAMA. 1997;277:1387–1390.
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
Dr.Sarma@works
– prothrombotic
Anticoagulant:
•GAGs/AT III
•TFPI
•Thrombomodulin
Procoagulant:
•Tissue factor
•Binding sites for
coagulation factors
and fibrin
Profibrinolytic:
•t-PA
•u-PA
•Binding sites for
plasminogen
•PA receptors
Antifibrinolytic:
•PAI
•TAFI
Platelet inhibitory:
•PGI2 (prostacycline)
•Nitric oxide
•ADPase
•Carbon monoxide
Platelet activating:
•vWF
•PAF
•Fibronectin
•Endothelin-1
•TXA2
Antithrombotic
Vasodilation
Prothrombotic
Vasoconstriction
ACUTE CORONARY SYNDROME
No ST Elevation
ST Elevation
NSTEMI
Unstable Angina
NQMI
QwMI
Myocardial
Infarction
Dr.Sarma@works
ACUTE CORONARY
SYNDROMES (ACS)
Dr.Sarma@works
CAUSES OF UA/NSTEMI
Thrombosis
Mechanical
Obstruction
.
 MVO2
Dynamic
Obstruction
Inflammation/
Infection
Thrombosis
Mechanical
Obstruction
.
 MVO2
Dynamic
Obstruction
Braunwald, Circulation
98:2219, 1998
Dr.Sarma@works
Inflammation/
Infection
ED MANAGEMENT OF
UA/NSTEMI
ST  ?
NO
Nondiagnostic ECG
Normal serum cardiac markers
Observe
Follow-up at 4-8 hours: ECG, cardiac markers
No recurrent pain;
Neg follow-up studies
Stress study to provoke
ischemia prior to discharge
or as outpatient
Neg: nonischemic
discomfort;low-risk UA/NSTEMI
Outpatient follow-up
Dr.Sarma@works
YES
ST and/or T wave changes
Ongoing pain
+ cardiac markers
Hemodynamic abnormalities
Recurrent ischemic pain or
+ UA/NSTEMI follow-up studies
Diagnosis of UA/NSTEMI
confirmed
+ UA/NSTEMI confirmed
ADMIT
Evaluate
for
Reperfusion
INITIATION OF
ATHEROCLEROSIS
Dr.Sarma@works
TYPES OF PLAQUES
Fibrous Cap
Media
Lumen
“Vulnerable”
Plaque
Lumen
- T-Lymphocyte
- Macrophage
- Foam cell
- Activated intimal
SMC
Lipid Core
“Stable”
Dr.Sarma@works
Plaque
Dr.Sarma@works
PATHOGENESIS
Molecular Basis
• Normally a fine balance exists between production of
collagen by smooth muscle cell & break down
• Impaired gene expression disturbs this balance
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PATHOGENESIS OF ACS
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TRIGGERS OF PLAQUE
RUPTURE
Vulnerable Plaque
Inflammatory
infiltrate
Plaque
Thin fibrous
cap
Lum
en
Large lipid
core
Spontaneou
s or
triggered
rupture
Non occlusive
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thrombus
Occlusive
thrombus
Non occlusive
thrombus
Occlusive
thrombus
Factors
limiting
thrombosis
• Minor
plaque
disruption • Silent
• High flow • Unstable
angina
•
fibrinolyti • Non-Qwave MI
c activity
• Sudden
Dr.Sarma@works
death
Factors
favoring
thrombosis
• Q-wave
MI
• Sudden
death
• Major plaque
disruption
• Vasospasm
low flow
• fibrinolytic
activity
• Procoagulant
state, such as
fibrinogen,
ACUTE CORONARY
SYNDROME
Triggering
activities of
patients
Acute Risk Factors of an
Arterial Pressure surge or
Vasoconstriction lead to
Plaque Disruption
Minor
Plaque
Disruptio
n
NonVulnerable
Vulnerable Atherosclero
Atherosclero tic Plaque
tic Plaque
Dr.Sarma@works
Major
Plaque
Disruptio
n
Acute Risk Factors of a
coagulability Increase or
Vasoconstriction lead to
occlusion by
Non-complete Occlusive
Occlusive Thrombus
Thrombu
Thrombus
s
Asymptomat
ic Unstable
Angina or
Non-Q-MI
Occlusive
Thrombu
s
Myocardia
l
Infarction
or Sudden
Cardiac
Death
UNSTABLE
PLAQUE
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LARGE NON OCCLUDING
THROMBUS DUE TO ENDOTHELIAL
EROSION
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NON OCCLUDING THROMBUS
DUE TO PLAQUE RUPTURE
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OCCLUSIVE THROMBUS DUE TO
PLAQUE RUPTURE
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HEALED PLAQUE
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PLATELET PLUG
FORMATION
ADP
Epinephri
ne
Adhesion
Thrombin Collagen
Arachidonic Acid
release
Aspiri
n
Thromboxane
A2
Release of
ADP, serotonin
Ticlopidine /
GP IIb/IIIa
Clopidogrel
exposure GP IIb/IIIa receptor
blockers
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Platelet
aggregation
GP IIb/IIIa
(quiescent)
Resting Platelet
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GP IIb/IIIa (activated)
Activated Platelet
GP IIb/IIIa (activated)
Fibrinogen
Platelet
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R.G.D.
Sequence
vWF
Competitive Antagonist
(Integrilin, Aggrastat)
Activated Platelet
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Thrombotic Process —
Pathophysiology
Plaque Characteristics & Disruption
Thrombus
Lumen
Fibrous Cap
Lipid-Rich
Core
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Thinning
Fibrous Cap Disruption
Production of LMWH by
depolymerization of unfractionated
heparin
Native heparin
Pentasaccharide
sequence
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Depolymerisation
process
LMWH
Semin Thromb. Hemost. 1993; 19
suppl. 1: 1-11
MODE OF ACTION OF
HEPARIN AND LMWH
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MODE OF ACTION OF
ANTIPLATELET AGENTS
Vessel Wall Injury
Cyclooxygenase
Arachidon
ic Acid
PGH2
TXA2
ADP
ASPIRI
N IIB
Fibrinog
en
Platelet
III
a
GP IIb,
IIIa
ADP Receptor
EC
Vessel wall
Dr.Sarma@works
TXA
CLOPIDOGREL
2
ADP
Lumen
Platelet
ANTI-PLATELET THERAPY
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Antiplatelet Agents
GP IIb/IIIa Inhibitors
GP IIb/IIIa
Receptor
Fibrinogen
GP IIb/IIIa
Inhibitors
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Oral Antiplatelet Agents
Mechanism of Action
ADP
clopidogrel bisulfate
ticlopidine HCl
dipyridamole
ADP
phosphodiesterase
ADP
Gp IIb/IIIa
(Fibrinogen
Receptor)
Activation
Collagen
Thrombin
TXA2
COX
TXA2
aspirin
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX =
Dr.Sarma@works
cyclooxygenase. Schafer AI. Am J Med. 1996;101:199–209.
Anticoagulants
Direct Thrombin Inhibitors
Hirudin-Thrombin Binding
Mechanisms of Thrombin Inhibition
Fibrin Binding Site
Thrombin
Catalytic
Site
Substrate
Recognition Site
Dr.Sarma@works
Thrombin
Hirudin
Thrombin
ATIII/
Heparin
The Management of Patients with
Acute Myocardial Infarction
Initial Assessment
and Evaluation
Dr.Sarma@works
Algorithm for Initial Assessment and Evaluation
of the Patient with Acute Chest Pain
Chest pain consistent with coronary ischemia
Within 10 minutes
• Initial evaluatioon
• 12 lead ECG
• Establish IV
• Aspirin 160-325 mg - chewed
• Establish continuous ECG monitoring
• Blood for baseline serum cardiac markers
Therapeutic/Diagnostic tracking according 12-lead ECG
Nondiagnostic / normal ECG
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ECG suggestive of ischemia T wave inversion or ST depression
ST segment elevation or new
bundle branch block
Emergency Department Algorithms/Protocol
for Patients with Symptoms and Signs of AMI
Onset of
symptoms
Ambulance presents
patient to ED lobby
Patient presents
to ED lobby
ED triage or charge nurse triages patient
• AMI symptoms and signs
• 12-lead ECG
• Brief, targeted history
Emergency nurse initiates emergency
nursing care in acute care area of ED
• Cardiac monitor
• Blood studies
• Oxygen therapy
• Nitroglycerin
• IV D5W
• Aspirin
Emergency Physician
evaluates patient
• History
• Physical exam
• Interpret ECG
AMI
patient?
Dr.Sarma@works
Emergency Department Algorithms/Protocol
for Patients with Symptoms and Signs of AMI
Yes
AMI
patient?
No
Uncertain
Yes
Fibrinolytic
therapy
Candidate
for fibrinolytic
therapy
Evaluate
further
Trans Mural
Consult
Conduct education and
follow-up instruction
No
Other indicated treatment:
• Other drugs for AMI
(beta-blockers, heparin,
aspirin, nitrates)
• Transfer to cath lab for
PTCA or surgery for CABG
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Admit
Release
Patient with Acute Chest Pain with
non-diagnostic and normal ECG
Non-diagnostic / normal ECG
• Continue evaluation/monitoring in
Emergency Department or Chest Pain Unit
• Serial serum cardiac marker levels - CKMB, Trop
• Serial ECGs
• Consider noninvasive evaluation of ischemia
• Consider alternative diagnoses
No Evidence of
MI or ischemia
MI or
demonstrable
ischemia
Discharge with
follow-up as
appropriate
(Goal: 12-24 hours)
Admit to unit of
appropriate intensity
Dr.Sarma@works
Patient with Acute Chest Pain with
T-wave inversion or ST depression
ECG suggestive of ischemia T wave inversion or ST depression
• Anti-ischemia Therapy
• Analgesia
Admit to unit of
appropriate intensity
Admission blood work
• CBC
• Electrolytes, BUN,
creatinine
• Lipid profile
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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 + Aspirin
Nitrates for recurrent angina
Antithrombins: LMWH - high-risk patients
Anti-Platelets: GpIIb/IIIa inhibitor
Patients without prior
beta-blocker therapy or
who are inadequately
treated on current dose
of beta-blocker
Establish adequate
beta-blockade
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Persistnet symptoms in
patients with prior
beta-blocker therapy or
who cannot tolerate
beta-blockers
Add calcium antagonist
Assess Clinical Status
High-risk patient:
1. Recurrent ischemia
2. Depressed LV function
3. Widespread ECG changes
4. Prior MI
Clinical stability
Catheterization: Anatomy
suitable for revascularization
Yes
No
PCI
CABG
Medical
Therapy
Modified from Antman EM. Atlas of Heart Disease, VIII; 1996
Continued observation
in hospital
Consideration of
stress testing
Patient with Acute Chest Pain with
ST elevation or new bundle branch block
ST segment elevation or new
bundle branch block
Assess suitability for reperfusion
• ? Contraindications for fibrinolysis
• Availability and appropriateness of primary angioplasty
Initiate anti-ischemia therapy
• Beta-blocker
• Nitroglycerine
Analgesia
Admission blood work
Initiate fibrinolysis
if indicated
Goal: 30 minutes
from entry to ED
Primary PTCA
if available and suitable
Goal: PTCA within
90 30 minutes
Admit - CCU
Dr.Sarma@works
The Management of Patients with
Acute Myocardial Infarction
Initial Management
Dr.Sarma@works
Management of Patients with ST
Elevation
ST elevation
Aspirin
Beta-blocker
 12 h
Eligible for
fibrinolytic therapy
Fibrinolytic therapy
contraindicated
Fibrinolytic therapy
Primary
PTCA or CABG
> 12 h
Not a candidate for
reperfusion therapy
Persistent
symptoms ?
No
Other medical therapy:
ACE inhibitors
? Nitrates
Anticoagulants
Dr.Sarma@works
Modified from Antman EM. Atlas of Heart Disease, VIII; 1996
Yes
Consider
Reperfusion
Therapy
Comparison of Approved Fibrinolytic
Agents
Streptokinase
Anistreplase
Alteplase
Reteplase
Dose
10U x 2
over 30 min
Bolus administration
Antigenic
Allergic reactions
(mostly hypotension)
Systemic fibrinogen
depletion
90-min patency rate
TIMI-3 flow
Mortality rate
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Cost /dose (US)
1.5 MU
30 mg
100 mg
in 30-60 min
in 5 min
in 90 min
NO
Yes
Yes
Yes
Yes
Marked
~50%
32%
7.3%
$294
Yes
No
No
Marked
~65%
43%
10.5%
$2116
No
Yes
No
No
Mild Moderate
~75% ~75%
54%
60%
7.2% 7.5%
$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
Dr.Sarma@works
ContraindicatIons and Cautions for
Fibrinolytic Used in Myocardial
Infarction
Cautions / Relative Contraindications
• Severe uncontrolled HTN on
presentation (BP >180/110
mmHg)
• History of prior CVA or known
intra-cerebral pathology not
covered in contraindications
• Current use of anticoagulants in
therapeutic doses (INR  2-3);
no bleeding diathesis
• Recent trauma (within 2-4
weeks) including head trauma
Dr.Sarma@works
• 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
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
Dr.Sarma@works
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
Dr.Sarma@works
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
Dr.Sarma@works
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
Dr.Sarma@works
Pharmacologic Management of Patients with
MI
Heparin Recommendations
Class I Recommendations
1. In patients undergoing percutaneous or surgical revascularization
Class IIa Recommendations
1. Intravenously in patients undergoing reperfusion therapy with
alteplase/reteplase (note change in recommendations)
1999
1996
Bolus Dose
60 U/kg
70 U/kg
Maintenance
~12 U/kg/hr
~15 U/kg/hr
Maximum
4000 U bolus
None
1000 U/h if >70kg
aPTT
1.5-2.0 x control
1.5-2.0 x control
(50-70 sec) for 48 hrs
(50-70 sec) for 48
hrs
Dr.Sarma@works
Pharmacologic Management of Patients with
MI
Heparin Recommendations
Class IIa Recommendations (continued)
2. Intravenous unfractionated heparin (UFH) or low molecular weight
heparin (LMWH) subcutaneously for patients with non-ST elevation
MI
3. Subcutaneous UFH (eg, 7,500 U b.I.d.) or low molecular weight
heparin (eg, enoxaparin 1 mg/kg b.I.d.) in all patients not treated with
fibrinolytic therapy who do not have a contraindication to heparin. In
patients who are at high risk for systemic emboli (large or anterior MI,
AF, previous embolus, or known LV thrombus), intravenous heparin is
prefered
4. Intravenously in patients treated with nonselective fibrinolytic agents
(streptokinase, anistrplase, urokinase) who are at high risk for systemic
emboli (large or anterior MI, AF, previous embolus, or known LV
Dr.Sarma@works
thrombus)
Pharmacologic Management of Patients with
MI
Heparin Recommendations
Class IIb Recommendations
1. In patients treated with nonselective fibrinolytic agents, not at high
risk, subcutaneous heparin, 7,500 U to 12,500 U twice a day until
completely ambulatory
Class III Recommendations
1. Routine intravenous heparin within 6 hrs to patients receiving a
nonselective fibrinolytic agent (streptokinase, anistrplase, urokinase)
who are not at high risk for systemic embolism
Dr.Sarma@works
Pharmacologic Management of Patients with
MI
GP IIb/IIIa Inhibitors - New
Recommendations
Class IIa Recommendations
1. For use in patients experiencing an MI without ST segment
elevation who have some high-risk features and/or
refractory ischemia, provided they do not have a
contraindication due to a bleeding risk
Dr.Sarma@works
Classification of Inotropic Agents
Agent
Mechanism Inotrpic Vascular Effect
Isoproterenol
-1 receptor
tobradycardia;
++
Major Use
Dilatation
Hypotension due
Dobutamine
-1 receptor
mm Hg
Dopamine
Low dose:
<90 mm Hg
(dopaminergic)
value
Medium dose:
(-1 receptor)
High dose:
(-receptor)
Norepinephrine - receptor
++
Mild dilatation
no pacing available
Low output with SBP >90
++
Renovascular dilatation
Hypoperfusion with SBP
++
Intense constriction
Intense constriction
Amrinone
failure of
++
Dilatation
PDE inhibitor
or 30 mm Hg below usual
Constriction
Extreme hypotension despite
dopamine use
Second-tier agent after
dopamine / dobutamine
Milrinone
PDE inhibitor
Digitalis
Inhibts Na+-K+
dysfunction
Dr.Sarma@works
++
+
Dilatation
Variable
Established systolic LV
The Management of Patients with
Acute Myocardial Infarction
Hospital Management
Dr.Sarma@works
Sample Admitting Orders
Condition
IV
Vital signs
Activity
Diet
Medications
Dr.Sarma@works
Serious
NS or D5W to keep vein open
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
Bed rest with bedside commode and progress as
tolerated after approximately 12 hrs
NPO until pain free, then clear liquids.
Progress to a heart - healthy diet
Nasal O2 2 L/min x 3 hrs
Enteric-coated aspirin daily (165 mg)
Stool softener daily
Beta-adrenoreceptor blockers
Consider need for analgesics, nitroglycerin, anxiolytic
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)
Dr.Sarma@works
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)
Dr.Sarma@works
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)
Dr.Sarma@works
Clinical Profile of Mechanical
Complications of Myocardial Infarction
Variable
Muscle
Ventricular
Free Wall
Paillary
Septal 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 Vwave in
Hi RV
diastolic pressure
PCW tracing
Dr.Sarma@works Modified from Labovitz AJ, et al. Cardiovasc Rev Rep. 1984; 5-948
Mortality: Medical
90%
90%
90%
Surgical
50%
Case report
40-90%
The Management of Patients with
Acute Myocardial Infarction
MI Management Summary
Dr.Sarma@works
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
Dr.Sarma@works
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, antiischemic, 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)
Dr.Sarma@works
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
Dr.Sarma@works
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
Dr.Sarma@works
Predictors of 30 day Mortality in Fibrinolysis
Patients
GUSTO Trial - 41,021 patients
Heart rate 12%
AMI Location 6%
Other 10% (DM, smoking, BP;
Height/Weight, Prior CVD;
Time to Rx; Choice of
fibrinolytic therapy;
US hospital)
Killip class 15%
Systolic BP 24%
Age 32%
Dr.Sarma@works
Circulation 1995; 91:1659-1668
Clinical Indications of High Risk At Predischarge
Present
Absent
Absent
Strategy I
Strategy II
Strategy III
Symptom-Limited Exercise Test
at 14-21 Days
Submaximal Exercise Test
at 5-7 Days
Markedly
Abnormal
Mildly
Abnormal
Markedly Abnormal
Mildly Abnormal
Negative
Negative
Exercise Imaging Study
Exercise Imaging Study
Reversible Ischemia
Reversible
Ischemia
No Reversible
Ischemia
Medical Treatment
Strenuous Leisure Activity or Occupation
Symptom-Limited Exercise Test at 3-6 Weeks
Markedly
Abnormal
Cardiac
Catheterization
Mildly
Abnormal
Negative
Exercise Imaging Study
Reversible
Ischemia
Dr.Sarma@works
No Reversible Ischemia
No Reversible
Ischemia
Medical Treatment
Recommendations for Hormone
Replacement Therapy (HRT) After Acute
MI
Class IIa Recommendations
1. HRT with estrogen and progestin for secondary
prevention of coronary events should not be given
de novo to postmenopausal women after AMI
2. Postmenopausal women who are already taking
HRT with estrogen plus progestin at the time of
AMI can continue their therapy
Dr.Sarma@works
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
Dr.Sarma@works
Algorithm for the Evaluation and Management
of Patients Suspected of Having an ACS.
Noncardiac Diagnosis
Chronic Stable Angina
Treatment as
indicated by
alternative diagnosis
See ACC/AHA/ACP
Guidelines for Chronic
Stable Angina
No recurrent pain;
Negative follow-up studies
Symptoms Suggestive of ACS
Possible ACS
Definite ACS
No ST elevation
Nondiagnostic ECG
Normal Initial serum
cardiac markers
ST and/or T wave changes
Ongoing pain
Positive cardiac markers
Hemodynamic abnormalities
Observe
Stress study to provoke ischemia
Follow-up
at 4-8 hours;
Consider evaluation of LV function if ischemia present
(Test may be performed prior to discharge or as outpatient) ECG, cardiac markers
Negative:
Potential diagnoses:
nonischemic discomfort
low-risk ACS
Arrangement for
outpatientfollow-up
Dr.Sarma@works
Positive:
Diagnosis of ACS
confirmed
ST elevation
Evaluation for
reperfusion therapy
Recurrent ischemic pain
or positive follow-up studies
Diagnosis of ACS confirmed
See ACC/AHA
Guidelines for
Acute MI
Admit to hospital
Manage via acute ischemia pathway
III. Hospital Care
A. Anti-ischemic Therapy
B. Antiplatelet and Anticoagulation Therapy
C. Risk Stratification
D. Early Conservative vs. Invasive
Strategies
Dr.Sarma@works
Acute Ischemic Pathway
Aspirin
Beta-blockers
Nitrates
Antithrombin regimen
GP IIb/IIIa inhibitor
Monitoring (rhythm and ischemia)
Early Invasive strategy
Immediate
angiography
12-24 hour
angiography
Recurrent Ischemia and/or
ST segment shift, or Deep T-wave Inversion,
or Positive cardiac markers
Early Conservative strategy
Patient
stabilizes
Recurrent
symptoms/ischemia
Heart failure
Serious arrhythmia
Evaluate LV function
EF < .40
Stress Test
EF  .40
Low risk
Not low risk
Follow on
Medical Rx
Dr.Sarma@works
A. Anti-Ischemic Therapy
Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia
and arrhythmia detection in patients with ongoing rest pain
2. Sublingual follow by intravenous nitroglycerin (NTG)
for immediate relief of ischemia and associated symptoms
3. Morphine sulfate intravenously when symptoms are not
immediately relieved with NTG or when acute pulmonary
congestion is present
4. A beta-blocker, with the first dose administered
intravenously if there is ongoing chest pain, followed by
oral administration, in the absence of contraindications
Dr.Sarma@works
A. Anti-Ischemic Therapy
Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia
and arrhythmia detection in patients with ongoing rest pain
2. Sublingual follow by intravenous nitroglycerin (NTG)
for immediate relief of ischemia and associated symptoms
3. Morphine sulfate intravenously when symptoms are not
immediately relieved with NTG or when acute pulmonary
congestion is present
4. A beta-blocker, with the first dose administered
intravenously if there is ongoing chest pain, followed by
oral administration, in the absence of contraindications
Dr.Sarma@works
A. Anti-Ischemic Therapy
Class I - Recommendations
1. Bed rest with continuous ECG monitoring for ischemia
and arrhythmia detection in patients with ongoing rest pain
2. Sublingual follow by intravenous nitroglycerin (NTG)
for immediate relief of ischemia and associated symptoms
3. Morphine sulfate intravenously when symptoms are not
immediately relieved with NTG or when acute pulmonary
congestion is present
4. A beta-blocker, with the first dose administered
intravenously if there is ongoing chest pain, followed by
oral administration, in the absence of contraindications
Dr.Sarma@works
B. Antiplatelet and Anticoagulation
Therapy
• When platelets are activated, the GP IIb-IIIa receptor
undergoes a change in configuration that results in binding
of fibrinogen to platelet receptors, resulting in platelet
aggregation. The efficacy of GP IIb-IIIa antagonists in
prevention of the complications associated with
percutaneous coronary intervention (PCI) has been
documented in numerous trials, many of which were
composed entirely or in large part of patients with UA.
Dr.Sarma@works
B. Antiplatelet and Anticoagulation
Therapy
Class III Recommendations
Intravenous Thrombolytic Therapy
in Non-ST Elevation MI
Dr.Sarma@works
D. Early Conservative Versus Invasive
Strategies
Class I - Recommendations
1.
An early invasive strategy is recommended in patients
with UA/NSTEMI and any of the following high-risk
indicators:
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.
Dr.Sarma@works
D. Early Conservative Versus Invasive
Strategies
Class I - Recommendations
e.
f.
High-risk findings on noninvasive stress testing
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
Dr.Sarma@works
IV. Coronary Revascularization
Recommendations for
Revascularization with PCI and
CABG in Patients with UA/NSTEMI
Dr.Sarma@works
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
Dr.Sarma@works
Recommendations for Revascularization
Class I - Recommendations
4. PCI or CABG for patients with 1- or 2- vessel
CAD without significant proximal left anterior
descending CAD but with a large area of viable
myocaridum and high-risk criteria on
noninvasive testing
5. PCI for patients with multivessel CAD with
suitable coronary anatomy, with normal LV
function, and without diabetes
Dr.Sarma@works
Recommendations for Revascularization
Class I - Recommendations
6. CABG with the internal mammary artery for
patients with multivessel CAD and treated
diabetes mellitus
7. Intravenous platelet GP IIb/IIIa inhibitor in
UA/NSTEMI patients undergoing PCI
Dr.Sarma@works
Unstable Angina - Definition
• angina at rest (> 20 minutes)
• new-onset (< 2 months) exertional angina
(at least CCSC III in severity)
• recent (< 2 months) acceleration of angina
(increase in severity of at least one CCSC
class to at least CCSC class III)
Canadian Cardiovascular Society Classification
Dr.Sarma@works Agency for Health Care Policy Research - 1994
Unstable Angina
pathogenesis
• Plaque disruption
• Acute thrombosis
• Vasoconstriction
Dr.Sarma@works
Unstable Angina
pathogenesis
• Plaque disruption
– Passive plaque disruption
soft plaque with high concentration of
cholesteryl esters and a thin fibrous cap
– Active plaque disruption
macrophage-rich area with enzymes that may
degrade and weaken the fibrous cap;
predisposing it to rupture
Dr.Sarma@works
Unstable Angina
pathogenesis
• Acute Thrombosis
– Vulnerable plaque
• disrupted plaque with ulceration
• occurring in 2/3 of unstable patients
• the exposed lipid-rich core abundant in
cholesteryl ester is highly thrombogenic
– Systemic Hypercoagulable State
• disrupted plaque with erosion
• occurring in 1/3 of unstable patients
Dr.Sarma@works
Unstable Angina
pathogenesis
• Vasoconstriction
– the culprit lesion in response to deep arterial
damage or plaque disruption
– area of dysfunctional endothelium near the
culprit lesion
– platelet-dependent and thrombin-dependent
vasoconstriction, mediated by serotonin and
thromboxane A2
Dr.Sarma@works
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
Dr.Sarma@works
Non-Q-Wave MI
clues to diagnosis
• Prolonged chest pain
• Associated symptoms from the autonomic
nervous system
– nausea, vomiting, diaphoresis
• Persistent ST-segment depression after
resolution of chest pain
Dr.Sarma@works
Prinzmetal’s Angina
clues to diagnosis
• Transient ST-segment elevation during chest
pain
• Intermittent chest pain
–
–
–
–
often repetitive
usually at rest
typically in the early morning hours
rapidly relieved by nitroglycerine
• Syncope (rare), Raynaud’s, migraine
Dr.Sarma@works
Unstable Angina
Anti-thrombotic Therapy
• Thrombolytics are not indicated
• “lytic agents may stimulate the thrombogenic
process and result in paradoxical aggravation of
ischemia and myocardial infarction”
Dr.Sarma@works
TIMI IIIB Investigators
Circulation 1994; 89:1545-1556
Recommendations for
Revascularization
Class I - Recommendations
• Discharge prescription details
Dr.Sarma@works
Fiban
incidence of intracranial bleeding
Study
Compound
Treatment (%)
Placebo Active
RESTORE
EPIC
Tirofiban
Abciximab
0.3
0.3
EPILOG
IMPACT II
Dr.Sarma@works
Abciximab
Integrelin
0.0
0.07
The EXCITE Trial Investigators
0.1
0.1
0.4
0.1
0.07
0.15
Heparin
Bolus
Bolus + Infusion
Low dose
High dose
Unstable Angina
Anti-platelet Therapy
• Summary
The question is no longer
“Is there a reason to use GP IIb/IIIa
inhibitors?” but “Is there a reason not to
use them?”
Eric Topol, MD
Dr.Sarma@works
Unstable Angina
Anti-coagulant Therapy
• Heparin
– recommendation is based on documented
efficacy in many trials of moderate size
– meta-analyses (1,2) of six trials showed a 33%
risk reduction in MI and death, but with a two
fold increase in major bleeding
– titrate PTT to 2x the upper limits of normal
Dr.Sarma@works
1. Circulation 1994;89:81-88
2. JAMA 1996;276:811-815
Unstable Angina
Anti-coagulant Therapy
• Low-molecular-weight heparin
advantages over heparin:
– better bio-availability
– higher ratio (3:1) of anti-Xa to anti-IIa
activity
– longer anti-Xa activity, avoid rebound
– induces less platelet activation
– ease of use (subcutaneous - qd or bid)
– no need for monitoring
Dr.Sarma@works
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
Dr.Sarma@works
N Eng J Med 1997;337:447-452
MITI: Mortality, Infarct Size, and
Time
P<0.001
P=0.04
12.0
11.2
10.0
Tx >70 minutes
from onset
8.7
Percent
8.0
6.0
4.9
4.0
2.0
1.2
0.0
Mortality
Adapted
from Weaver WD, et al. JAMA. 1993;270:1211-1216.
Dr.Sarma@works
Tx <70 minutes
from onset
Infarct Size
Importance of Door-to-Balloon
Time:
30-Day Mortality in the GUSTOP=0.00 IIb Cohort
1
25
14.1
Mortality (%)
20
15
6.4
10
3.7
5
4.0
1.0
0
< 60
61-75
76-90
> 91
Door-to-Balloon Time (minutes)
Berger
PB, et al. Circulation. 1999;100:14-20.
Dr.Sarma@works
PTCA not
performed
Patency and Mode of Reperfusion
100
Patency Rate (%)
Fibrinolysis
80
60
90-minute
patency
40
PTCA at 75
minutes
20
PTCA at 120
minutes
0
0
30


ED
Drug
arrival administration
45
60
75
Time (minutes)
Adapted from Gibson CM. Ann Intern Med. 1999;130:841-847.
90
120
150
The Four Ds
ED Time Point 4:
DRUG
ED Time Point 3:
DECISION
ED Time Point 2:
DATA
ED Time Point 1:
DOOR
Time Interval III
Decision to drug
Time Interval II
ECG to decision to treat
Time Interval I
Door to ECG
Time of Onset
NHAAP
Recommendations. U.S. Department of Health NIH Publication: 1997:97-3787.
Dr.Sarma@works
ACC/AHA Guidelines for the
Management of Patients With
AMI
ST-segment elevation
Aspirin, beta-blocker, antithrombin
12 h
Eligible for
fibrinolytic
therapy
Fibrinolytic
therapy
Fibrinolytic
therapy
contraindicated
>12 h
Not a candidate
for reperfusion
therapy
Persistent
symptoms?
No
Primary PTCA or
CABG
Other medical therapy:
ACE inhibitors? Nitrates
Yes
Consider
reperfusion
therapy
PTCA, percutaneous transluminal coronary angioplasty; CABG,
coronary artery bypass graft; ACE, angiotensin-converting enzyme.
Adapted from Ryan TJ, et al. ACC/AHA 1999 Update.
Dr.Sarma@works
Available
at http://www.acc.org/clinical/guidelines and http://www.americanheart.org. Accessed February 2000.
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 doorDr.Sarma@works
to-drug time
Myocardial Infarction
Overview
•
Estimated 200-300,000 sudden (out-of-hospital)
deaths per year in U.S.
•
Approximately 1 million hospitalizations per year in
U.S.
•
Absolute number of MI events and fatality rates
declining
•
Remains principal cause of death in Western world
Acute MI
Impact of Modern Critical Care on Mortality
40
30
Short-Term Mortality (%)
30
20
15
10
0
Defibrillation
Hemodynamic
Monitoring
-Blockers
Pre-CCU
Era
CCU
Era
Aspirin
Thrombolysis
PTCA
6.5
Reperfusion
Era
Adapted from Antman, Braunwald In:Braunwald ed. Heart Disease p 1184.
Management of Acute MI
 Diagnosis
 Risk Stratification
 Acute Therapy
 Reperfusion
 Adjunctive
 Complications
 Pre-Discharge
Management
Diagnosis of Acute MI
History
•
Classic symptoms: intense, oppressive
chest pressure radiating to left arm
•
Other symptoms:
 chest heaviness, burning
 radiation to jaw, neck, shoulder, back,
arms
 nausea, vomiting
 diaphoresis
 dyspnea
 lightheadedness
•
Symptoms may be mild or subtle
Diagnosis of Acute MI
Physical Examination
•
Tachycardia or bradycardia
•
Extrasystoles
•
S3 or S4, mitral regurgitation
murmur
•
Lung rales
•
Hypertension or hypotension
•
Pallor, distress
Diagnosis of Acute MI
Electrocardiogram
Defines location, extent, and prognosis of
infarction
•
ST elevation diagnostic of coronary
occlusion
•
Q-waves do NOT signify completed infarction
•
ST depression or T inversion: unlikely total
coronary occlusion
•
ST elevation in RV4 for RV infarction
•
Observe up to 24 hrs for non-diagnostic ECG
•
Differentiate from early repolarization in V1-2
Acute MI
Myocardial Enzymes
CPK
Troponin
20
100
% of Patients
TnT >0.1 ng/ml
80
15
TNT <0.1 ng/ml
60
10
12.3
11.6
40
Occl -Reperf
20
Occl +Reperf
5
4.1
Subtot Occl
0
8-11 12-15 >16
4-7
<4
Time to Peak CK Activity (hrs)
Gore et al. AJC 1987;59:1234.
0
2.3
CK-MB>7 CK-MB<7
Ohman et al. NEJM 1996;335:1333.
Diagnosis of Acute MI
Echocardiography
•
Not diagnostic, but supportive
•
Identify regional wall motion abnormalities
•
Absence of contralateral wall hyperkinesia
suggests multivessel disease or IRA
recanalization
•
Assess LV function, prior infarcts
•
More sensitive than ECG for RV infarction
Diagnosis of Acute MI
Differential Diagnosis
Ischemic Heart Disease
• angina, aortic stenosis, hypertrophic CMP
Nonischemic Cardiovascular Disease
• pericarditis, aortic dissection
Gastrointestinal
• esophageal spasm, gastritis, PUD,
pancreatitis, cholecystitis
Pulmonary
• pulmonary embolism, pneumothorax,
pleurisy
Diagnosis of Acute MI
Coronary Angiography
•
May be necessary for equivocal symptoms
and ECG
e.g. patients with prior CABG, previous MI,
myocarditis with diffuse ECG D’s, noncharacteristic D’s on ECG
•
Finding of acutely-occluded vessel diagnostic
•
Allows mechanical reperfusion
Acute MI
Coronary Angiography
•
Incorporated in primary, rescue PTCA
strategies
•
If  ischemia, spontaneous or exerciseinduced or complicated (CHF, arrhythmia)
•
Controversial if uncomplicated MI
• Delineates anatomy but may potentiate
unneeded revascularization
• Very low risk but appreciable cost
• Key prognostic indicator
Management of Acute MI
 Diagnosis
 Risk Stratification
 Acute Therapy
 Reperfusion
 Adjunctive
 Complications
 Pre-Discharge
Management
Acute MI - Risk Stratification
The GUSTO Pyramid - 30 Day Mortality Model
HX
CV Disease
(0.4%)
HTN (0.6%)
Prior CABG (0.8%)
Accel t-PA (0.8%)
Smoker (0.8%)Weight (0.8%)
Diabetes (1%)Time-to-Rx (1%)
Age x Killip (1.3%) Height (1.1%)
MI Location (6%) Prior MI (3%)
Heart Rate (12%)
Killip Class (15%)
Systolic Blood Pressure (24%)
Age (31%)
Lee et al. Circulation 1995;91:1659-1668
Acute MI - Risk Stratification
ECG Classification - GUSTO I Outcome
Category
Occlusion Site
ECG
1-Year
Mortality
1.
Prox LAD
before septal
 ST V1-6, I, aVL 25.6%
fasicular or BBB
2.
Mid LAD
before diagonal
 ST V1-6, I, aVL 12.4%
3.
Distal LAD
Diagonal
beyond diagonal
in diagonal
 ST V1-4 or 10.2%
 ST I, aVL, V5-6
4.
Moderate-to- proximal RCA
large inferior
or LCX
(post, lat, RV)
 ST II, III, aVF and 8.4%
V1, V3R, V4R or
V5-6 or
R > S V1-2
5.
Small inferior
 ST II, III, aVF only6.7%
distal RCA or
LCX branch
Acute MI - Risk Stratification
Ejection Fraction
50%
Mortality (2-Year)
40%
30%
20%
10%
0
20
30
40
50
60
Ejection Fraction (%)
Gottlieb et al. Am J Cardiol 1992;69:977-984
70
Acute MI - Risk Stratification
Hemodynamic Subgroups - Killip Class
GISSI-1 (%)
Killip
Definition
Incidence
Control
I
No CHF
71
7.3
5.9
II
S3 gallop or
basilar rales
23
19.9
16.1
III
Pulmonary edema
(rales >1/2 up)
4
39.0
33.0
IV
Cardiogenic shock
2
70.1
69.9
Class
tality
Lytic
MortalityMor
Management of Acute MI
 Diagnosis
 Risk Stratification
 Acute Therapy
 Reperfusion
 Adjunctive
 Complications
 Pre-Discharge
Management
Aspirin in Acute MI
ISIS-2
20
35 Day Mortality (%)
15
13.2
10
10.7
10.4
8
5
0
4300
4295
4300
4292
Placebo
ASA
SK
SK + ASA
ISIS-2 Collaborative Group, Lancet 1988;2:349.
Aspirin in Acute MI
Recommendations
•
Indicated in ALL patients with acute MI,
except for true aspirin allergy (not
intolerance)
•
Initiate orally with chewable compound,
at least 160 mg stat
some data suggest first dose should
be
650 mg to achieve full antiplatelet
effect
Heparin for Acute MI?
Death
HeparinAllocated
ControlAllocated
Odds Ratio & 95% C.I.
t-PA
(4.3%)
17/476 (3.6%)
20/468
SK/APSAC
(7.2%)
28/402 (7.0%)
28/389
Aspirin
(4.8%)
30/622 (4.8%)
29/609 0.36
No Aspirin
15/256 (5.9%)
20/248
114/476 (23.9%)
83/468
0.43
(8.1%)
Any Bleeding
t-PA
(17.7%)
SK/APSAC
(14.4%)
0.5
85/402 (21.1%)
56/389
1.0
1.5
2.0
2.5
Heparin Better Control Better
Mahaffey, et al. AJC 77:551–6, 1996
T-PA and Heparin
100
80
Patency (%)
Heparin
79
79
No Heparin
83
82
75
71
60
80
80
52
40
44
20
0
Angio
TAMI-3
90 min
+ASA
HART
18 hrs
+ASA
Bleich
40 hrs
+ASA
ECSG-6
NHF
80 hrs 7 days
+ASA +ASA
Topol EJ, Textbook Intervent Cardiol, 2nd Ed, 1993, p. 83.
Acute MI
Heparin
•
Intravenous heparin recommended with tPA
(intial bolus 5000 U, infusion 1000 U/hr,
adjust for weight < 50 kg)
•
No clear data for benefit with streptokinase
and increased bleeding
•
Discontinue after 24 hrs, except for:
 atrial fibrillation
 recurrent ischemia
 anteroapical MI for CVA prophylaxis
Acute MI
IV Heparin
•
Optimal aPTT appears to be 50 to 70 seconds
•
Not indicated with streptokinase
GISSI-2/Int’l and ISIS-3
SK+ASA=SK+ASA+SQ hep
GUSTO-I
SK+IV hep = SK+SQ
hep
•
 Risk (at higher levels) of ICB
GUSTO-II
Adjunctive Therapy for Acute MI
Beta Blockers (Prior to Thrombolytic Era)
Pooled Analysis - 7 Day Outcome
5
4
3
% of Patients
p<0.02
4.2
3.6
> 29,000 Patients (26 Trials)
Beta Blocker
p<0.02
3.4
2.8
2
1
0
Placebo
p<0.05
2.2
2.6
-13%
-20%
-15%
Death
Reinfarction
Arrest (VF)
Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.47.
TIMI 2
Immediate vs Deferred Metoprolol
30
% of Patients
% of Patients
2
Immediate
20
1.5
Delayed
p<0.01
21
15
10
p<0.02
2
0
4
Reinfarction Recurrent Ischemia
1.4
1
p<0.03
0.5
0
0.28
IC Hemorrhage
48% of patients eligible for randomization to beta blocker
10% discontinued due to hypotension or bradycardia
TIMI Study Group. N Engl J Med 1989;320:618.
Beta Blockers in Acute MI
Pooled Analysis of Randomized Trials
Mortality Odds Ratio & 95%
CI
Study
Agent
ISIS-1
Atenolol 16,027

During
MI MIAMI
Metoprolol5,778

TIMI IIB
Post
MI

Metoprolol1,434
Norwegian Timolol
BHAT
N

1,884

3,837
Propranolol
0
Rx Better
Hennekens et al. NEJM 1996;335:1660.
1
Control Better
2
Beta Blockers in Acute MI
Recommendations
•
IV to oral beta blocker therapy in patients
without contraindications in first 24
hours
•
Avoid early therapy in patients with
bradycardia, hypotension, inferior MI,
CHF, impaired LV function, AV block,
asthma
•
Continue treatment for at least 2-3 years
Adjunctive Therapy for Acute MI
ACE Inhibitors
Outcome in “Megatrials”
15
% Mortality (4-6 Weeks)
ACE-I
10
0
Mortality Reduction = 5 lives/1000 Rx’d
p=0.57
Control
p=0.02
5
Total 85,064 Patients
6.87 7.33
p=0.03
6.33
9.39 9.72
7.11
27,442 27,382
9435 9460
5666 5679
ISIS-4
GISSI-3
Chinese
ACE Inhibitors in Acute MI
Pooled Analysis of Randomized Trials
Study
Agent
ISIS-4
Captopril 58,050
Mortality Odds Ratio & 95%
CI
N

During GISSI-3
Lisinopril 19,394
MI
CONSEN II Enalaprilat6,090
Post
MI
SAVE
Captopril 2,231
AIRE
Ramipril
TRACE
1,749
Trandolapril




2,006

0
Rx Better
Hennekens et al. NEJM 1996;335:1660.
1
Control Better
2
Adjunctive Therapy for Acute MI
Magnesium
LIMIT-2
ISIS-4
% Mortality (28 Day)
15
% Mortality (35 Day)
15
p < 0.05
10
p = NS
10.20
10
7.80
5
5
0
0
Mg
Placebo
Woods et al.
Lancet 1992;339:1553.
7.28
6.92
Mg
Placebo
ISIS-4 Collab Group
Lancet 1995;345:669.
Magnesium in Acute MI
Summary
• Mortality benefit of empiric Rx - conflicting
results
of randomized trials
 possibly due to late administration and
low mortality in the ISIS-4 trial
• Correct low serum [Mg+2]
• Magnesium 1-2 gm bolus over 5 minutes may
be definitive Rx for Torsade de Pointes or
polymorphic ventricular tachycardia
Adjunctive Therapy for Acute MI
Calcium Channel Antagonists
Agent
N
Odds Ratio & 95% CI

Nifedipine 1358
Verapamil 1775


Diltiazem 2466
Verapamil/ 4241
Diltiazem
Pooled
Ca+2Ant Control


5599
0
Less Mortality
1
More Mortality
15.0%
13.0%
10.8%
13.3%
13.5%
13.5%
12.4%
13.4%
13.0%
13.3%
2
Held et al, in Topol: Text Int Cardiol 2nd Ed 1993, p.52.
Management of Acute MI
 Diagnosis
 Risk Stratification
 Acute Therapy
 Reperfusion
 Adjunctive
 Complications
 Pre-Discharge
Management
Complications of Acute MI
Extension / Ischemia
Expansion / Aneurysm
Mechanical
Arrhythmia
Pericarditis
Acute MI
Heart Failure
RV Infarct
Mural Thrombus
Management of Acute MI
Intra-Aortic Balloon Pump Counterpulsation
Decreases systemic afterload
Increases diastolic aortic
pressure

Reduces myocardial oxygen demand

Improves systemic / end-organ
perfusion

Variable effects on coronary
perfusion
IABP in Acute MI
Indications
 Cardiogenic shock not quickly reversed
(indication less firm for hemodynamic
instability without shock)
 Acute MR or VSD
 Refractory myocardial ischemia
 Refractory ventricular arrhythmias
Useful as a bridge to revascularization and for
support during recovery of extensive “stunned
myocardium”
Management of Acute MI
Indications for Invasive Hemodynamic Monitoring
Right Heart Catheterization (Swan-Ganz Catheter)
 Severe or progressive CHF or pulmonary
edema
 VSD or papillary muscle rupture
 Cardiogenic shock or progressive
hypotension
 Hypotension unresponsive to fluid Rx
 Need for inotropic or IABP support
 RV infarction
 Refractory VT
Acute MI - Recurrent Infarction /
Ischemia Pathophysiology
•
In distribution of infarct vessel:
 IRA reperfusion, then reocclusion
 thrombus propogation, branch occlusion
 distal embolization
 reduced coronary perfusion pressure with
severe residual IRA stenosis
 reduced collateral flow from stenosed artery
•
At a distance:
 reduced collateral flow from IRA
 new coronary thrombus (hypercoagulable
state)
 reduced systemic perfusion pressure
 increased myocardial oxygen consumption
Acute MI - Complications
Recurrent Ischemia / Infarction
•
Prevention:
 Aspirin
 Beta blockers
 ACE inhibitors with low LVEF
 ? heparin with fibrin-specific lytics
(reocclusion)
•
Treatment:
 Pharmacologic (beta blockers, nitrates)
 IABP
 Urgent revascularization
 Repeat lytics (antibodies to SK)
Acute MI - CHF and Shock
Pathophysiology
•
Extensive (or multiple) LV infarction(s) - systolic
dysfunction
•
Impaired relaxation, compliance due to infarction or
ischemia - diastolic dysfunction
•
Extensive RV infarction or ischemia
•
VSD or acute severe MR
•
Tamponade (w/ or w/o free wall rupture)
•
Others
e.g. critical valve stenosis or regurgitation, toxicmetabolic, sepsis, beta- or Ca+2-blocker overdose,
pulmonary embolism, bowel ischemia
Acute MI - CHF and Shock
Hemodynamic Subsets
Subset
PCWP
CI
(mm Hg) (l/min)
Clinical Setting
1
< 18
> 2.2
asymptomatic
2
congestion
> 18
> 2.2
pulmonary
3
< 18
< 2.2
4
> 18
< 2.2
RV failure,
hypovolemia, or
profound venodilation
severe LV dysfxn
cardiogenic shock
Forrester JS et al. NEJM 1976;295:1356 and 1404.
Acute MI - Cardiogenic Shock
Outcome with PTCA
Pooled Analysis of 22 Retrospective Studies
100
Mortality (%)
80
81
•
Historical
control
mortality ~ 80%
•
Total 646 pts
•
PTCA success
rate = 76%
60
40
45
33
20
0
Total
Successful Unsuccessful
PTCA
PTCA
Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 461.
Acute MI - Mechanical Complications
Free Wall Rupture
•
Less frequent (1-3.4%), but earlier, with
thrombolysis
•
Uncontained  sudden EMD or asystole
•
Pseudoaneurysm  transient hypotension,
EMD, bradycardia, repetitive emesis,
restlessness
•
Echocardiogram usually diagnostic
•
Surgical repair - may require pericardiocentesis
for uncontained rupture
Acute MI - Mechanical Complications
Interventricular Septal Rupture
•
Incidence 1-3% of transmural MIs
•
Acute shock, pulmonary edema, right heart failure,
new loud pan-systolic murmur (thrill in 50%)
•
Diagnose with echocardiogram or O2 saturation
step-up
•
Medical stabilization and IABP for CHF, shock
•
Early surgical repair for decompensated pts;
mortality highest in pts with inferior MI and complex
ruptures involving RV (~70%), lowest for apical
ruptures (~30%)
Acute MI - Complications
Infarct Expansion
•
Potential consequences:
 LV aneurysm +/- mural thrombus +/embolization
 adverse LV remodeling and CHF
 ventricular rupture
 ventricular arrhythmias
•
Prevention:
 ACE inhibitors
 ? nitrates
 the “open artery”
Acute MI
The “Late Open Artery”
n
Patent
Up
Time to
FollowOccluded
Angio
(days) (months)
IRA
IRA
Mortality Mortal
ity
Cigarroa
179
1-150
47
0%
18%
Gohike
102
< 365
51
13%
17%
Galvani
172
10
43
1%
17%
White
305
28
39
5%
10%
Lamas
946
4
42
14%
24%
Welty
Hochman, Gersh in Topol, Text Cardiovasc Med 1998, p. 445.
479
< 90
34
4%
17%
Acute MI - Mechanical Complications
Acute Mitral Regurgitation
•
Transient MR common in early MI (20-40%)
•
Associated with advanced age, prior MI, infarct
extension, recurrent chest pain, CHF, female gender
•
Persistent MR, even mild, associated with increased
long-term mortality post-MI
•
May be due to papillary muscle or chordal rupture
or to geometric changes (dilation) of ventricle and
annulus
•
Most common with inferior MI (single blood supply
to posteromedial papillary muscle) - MI often small
Acute Mitral Regurgitation
Diagnosis and Management

harsh, short systolic murmur - may be muffled

sudden CHF +/- hypotension or shock 2-7 days
post MI

echocardiography (surface or TEE) usually
diagnostic - mobile papillary muscle head or flail
MV leaflet

LV function often normal or hyperkinetic

sudden hemodynamic deterioration common

stabilize medically, IABP, then surgical repair

surgical mortality high if shock is present
Acute MI - Complications
Right Ventricular Infarction
•
Associated with occlusion of proximal RCA
•
Classic triad by hypotension, JVP, clear lungs
specific but insensitive
•
Kussmaul’s sign, JVP > 8 cm H2O sensitive and
specific
•
EKG: ST in RV4
•
Echo: RV dilation and hypokinesia
•
PA catheter: RA >10 mm, RA/PCWP ratio > 0.8
Acute MI - RV Infarction
Management
•
Extensive irreversible infarction is unusual transient ischemic dysfunction with long-term
recovery common
•
Marked by sensitivity to preload reduction
(nitrates, diuretics, morphine), bradycardia, AV
block
•
Fluid volume infusion for hypotension and low
cardiac output
•
PCWP elevation may occur due to septal shift
•
Dobutamine if fluids  RA and PCWP without
Acute MI - Arrhythmias
Prophylactic Lidocaine
•
Prophylactic use for suppression of VT or VF
controversial
•
Overview of randomized trials:
 33% reduction in primary ventricular arrhythmias
 trend toward 38% increased mortality (asystole)
•
Potential benefit in reperfusion era - GUSTO I (but not
a randomized comparison)
•
Should likely avoid unless VT / VF or non-sustained VT
occurs
Acute MI - Antiarrhythmic Agents
Pooled Analysis of Randomized Trials
Study
Agent
CAST
Enc / Flec 1,498
Class
CAST II
I

Moricizine 1,325
EMIAT
Amiodarone1,486
CAMIAT
1,202
Amiodarone
Class
III
SWORD
Mortality Odds Ratio & 95%
CI
N




d-Sotalol 3,121
Julian et al l-Sotalol

1,456
0.1
Rx Better
1
Control Better
NEJM 1996;335:1660. Lancet 1997;349:667 and 675.
10
Acute MI - Arrhythmias
Ventricular Tachycardia or Fibrillation
•
Prognosis of VT or VF in first 48 hours
controversial
 MILIS - no increased in-hospital mortality
 GISSI - increased in-hospital mortality
 No increased mortality after hospital
discharge
•
VT or VF after first 48 hours associated with
poorer long-term prognosis
•
Acute management - K+ replacement,
antiarrhythmic therapy (lidocaine,
procainamide, or amiodarone) if stable,
electrical shock if unstable
Acute MI - Arrhythmias
Atrial Fibrillation
•
Incidence reduced with thrombolysis (<5%)
•
Associated with large MI (especially if sustained)
•
Prognostic of adverse events over following year
•
Rate control with digoxin, or (without CHF) beta
blockers, verapamil, or diltiazem
•
Consider IV amiodarone
•
Electrical cardioversion for hemodynamic
compromise
or ischemia
Acute MI - Arrhythmias
Indications for Temporary Pacing
 asystole
 complete (third-degree) AV block
 second-degree Mobitz II AV block
 second-degree Mobitz I AV block with
hypotension
 new bifascicular block, esp with first-degree AV
block
 symptomatic bradycardia, unresponsive to
atropine
Acute MI - Arrhythmias
Indications for Permanent Pacing
 persistent complete (third-degree) AV block
 persistent sinus node dysfunction symptomatic bradycardia
 intermittent second-degree Mobitz II or thirddegree AV block
 second-degree Mobitz II or third-degree AV
block with new bundle branch block
Management of Acute MI
 Diagnosis
 Risk Stratification
 Acute Therapy
 Reperfusion
 Adjunctive
 Complications
 Pre-Discharge
Management
Acute MI
Pre-Discharge Management
•
Risk stratification
•
Catheterization and revascularization
strategy
•
Electrophysiologic evaluation for VT or VF
•
Lifestyle modification: diet, exercise,
tobacco
•
Pharmacologic therapy
Acute MI - Risk Stratification
Post-MI Revascularization Strategy
Low Risk
High Risk*
 LVSF
Nl LVSF
Stress Imaging
 LVSF
Nl LVSF
Stress Imaging
or
Catheterization
Normal
Angiography
±
Revascularization
Direct
Cath
* (Re) MI or CP, VT, CHF, Prior MI, Prior Revascularization
Acute MI Management
Pharmacologic Therapy on Hospital Discharge
 Aspirin indefinitely (ticlopidine or clopidogrel
for aspirin allergy or intolerance)
 Beta blockers for at least 2-3 years
 ACE inhibitors for CHF, LVEF<40%, or large
infarction (even with preserved LVEF)
 Lipid lowering agents
 Coumadin for mural thrombus, extensive
anterior infarct, DVT, atrial fibrillation
Thrombolysis in Acute MI
Relative Contraindications
 Uncontrolled HTN (BP > 180/110) on
presentation
 History prior CVA beyond 1 yr
 Anticoagulant Rx with INR > 2-3; bleeding
diathesis
 Recent trauma (within 2-4 wks)
 Noncompressible vascular punctures
 Recent internal bleeding (within 2-4 wks)
 Pregnancy
 Active peptic ulcer
 Prior exposure (5 day - 2 yr) for SK or APSAC
Thrombolysis in Acute MI
Absolute Contraindications
 Previous hemorrhagic stroke
 CVA within previous yr
 Intracranial neoplasia or AVM
 Active internal bleeding (not
menses)
 Suspected aortic dissection
Myocardial Reperfusion
The Original Paradigm
Re-establish
Infarct Vessel
Patency
Limit Infarct
Size
 Mortality
GUSTO
8
Mortality Trial
Angiographic Trial
41,021 Patients
30-day Outcome
2,431 Patients
TIMI 3 flow
% Mortality
60
50
6
4
2
0
% of Patients
54
40
SK (IV)
SK (SubQ)
t-PA +SK
Accel.t-PA
0 2 4 6 8 1012141618202224262830
Days from Randomization
30
20
29
33
38
10
0
SK+SQ SK+IV Accel. t-PA+
Hep Hep t-PA SK
Thrombolytic: Placebo-Control
Meta-Analysis
Agent
Ratio
s.d.)
Streptokinase
Trial Name
Reduction
Deaths/Patients
Active
495/4865
GISSI
23% ± 6
ISAM
50/842
16% ± 18
ISIS-2
471/5350
30% ± 5
Control
623/4878
Odds
Odds
(& 95% Cl)
(±
61/868
648/5360
APSAC
AIMS
50% ± 16
32/502
61/502
t-PA
ASSET
28% ± 9
182/2516
245/2495
0.0
0.5
1.0
1.5
2.0
Lytic better
Lytic worse
Overall: any thrombolytic 1230/14075 1623/14103
Thrombolysis for Acute MI
Time to Therapy and Mortality Reduction
Pooled Analysis of Randomized Trials
Absolute Mortality Reduction per 1000 Patients
40

30

20


10

0
0
6
12
18
24
Time from Symptom Onset to Randomization (h)
Fibrinolytic Therapy Trialists. Lancet 1994;343:311.
New Fibrinolytics
ASSENT II
8
30 Day Outcom e (%)
8
7
t-PA
6
TNK
6.15 6.17
INTIME II
6
5
4
4
3
3
2
2
1
1
0
Mortality
ICH
t-PA
7
5
0.94 0.93
30 Day Outcom e (%)
0
6.6
6.77
TNK
p=0.003
1.13
Mortality
0.62
ICH
Thrombolysis for Acute MI
Electrocardiographic Criteria for Therapy
Pooled Analysis of Randomized Trials
EKG
Odds Ratio & 95% CI
Placebo Lysis
BBB

23.6%
18.7%
ST Anterior

16.9%
13.2%
8.4%
7.5%
13.4%
10.6%
13.8%
15.2%
5.8%
5.2%
2.3%
3.0%
ST Inferior

ST Other

ST


Other Abnorm
Normal

0.33
Lysis Better
1
Placebo Better
3
Fibrinolytic Therapy Trialists. Lancet 1994;343:311.
Thrombolysis and Age
40
GISSI -1 and ISIS -2
GUSTO 1
N = 28,896 Patients
N = 41,021 Patients
% Mortality
Placebo
30
20
10
Streptokinase
14% RR 
D = 2.4%
26% RR 
D = 1.2%
7.7
0
14% RR 
D = 3.9%
28.8
40
SK
30
Accel t-PA
6% RR 
D =1.3%
24.9
20
17.6
15.2
10
21.5
20.2
17% RR 
D = 1.0%
6.0
5.5
<65
% Death or Disabling Stroke
65-74
Age (yrs)
75+
0
5.0
<=75
>75
Age (yrs)
Acute MI
PTCA vs Lysis
Death + MI (%)
20
Thrombolysis
PTCA
15
10
5
p<0.0001
0
0
11 RCTs (2725 patients)
4
2
Months from Randomization
6
PCAT Collaborative Group, 2001
Primary Angioplasty in Acute MI
Pooled Analysis of Randomized Trials
Trial
SK
Trials
t-PA
Trials
Accel
t-PA
Trials
N
Odds Ratio & 95% CI
Zijlstra 389
Ribeiro 100
Grinfeld 112
DeWood 90
395
PAMI
Gibbons 103
Ribichini 83
Elizaga 189
GUSTO II1138
Pooled 2599
0.1
PTCA Lysis








Pooled 32% RR

PTCA Better
1
Lysis Better
2.0% 7.4%
6.0% 2.0%
9.3% 10.3%
6.5% 4.5%
2.6% 6.5%
4.3% 3.6%
0.0% 2.4%
3.2% 10.6%
5.7% 7.0%
4.4% 6.5%
10
Topol, Van de Werf. Textbook Cardiovasc Med 1998;p416
Acute MI: 1995
RESCUE
156 pts < 8 hours chest pain, ant. MI with occluded LAD
PTCA successful in 92% of patients
Outcomes at 30 Days
20
% of Patients
50
Control
16
40
16.6
Rescue
12
8
4
0
%
39
38
40
43
30
9.6
20
7.0
5.1
Death
6.4
1.3
Severe CHF Death or CHF
10
0
Rest EF
Exercise EF
Pathophysiology of Combination Therapy in AMI
Combination Therapy
 Thrombus
 % Stenosis
 Minimum Diameter
 Epicardial Flow
Reduces
Reinfarction*
 Myocardial Blush
 ST Resolution
Facilitates PCI
*Gibson et al. J Am Coll Cardiol. 1995;25:582-589.
Gibson et al. Circulation. 2001;103:2550-2554.
 Myocardial Flow
Recent Clinical Trials
Trial
GUSTO-V
Lytic
GP IIb/IIIa
Receptor Inhibitor Anticoagulant
100% r-PA
50% r-PA
None
Abciximab
Standard-dose heparin
Low-dose heparin
ASSENT-3 100% TNK-tPA
50% TNK-tPA
100% TNK-tPA
None
Abciximab
None
ACC/AHA heparin dose
Low-dose heparin
Enoxaparin
ENTIRE
Abciximab
Abciximab
None
None
Unfractionated heparin
Enoxaparin
Unfractionated heparin
Enoxaparin
50% TNK-tPA
50% TNK-tPA
100% TNK-tPA
100% TNK-tPA
Clinical Trials: Ongoing
Trial
Lytic
GP IIb/IIIa
Receptor Inhibitor Anticoagulant
FASTER
50% TNK-tPA
75% TNK-tPA
100% TNK-tPA
Tirofiban
Tirofiban
Tirofiban
Low-dose heparin
Low-dose heparin
Low-dose heparin
INTEGRITI
50% TNK-tPA
75% TNK-tPA
100% TNK-tPA
Eptifibatide
Eptifibatide
Eptifibatide
Low-dose heparin
Low-dose heparin
Low-dose heparin
GUSTO-I: A 20% Increase in TIMI Grade 3 Flow
is Needed to Yield a 1% Mortality Reduction
% TIMI Grade 3 Flow
60
54%
50
t-PA
6.3%
40
32%
30
20
SK
7.4%
10
0
t-PA
SK
5
6
The GUSTO Angiographic Investigators. N Engl J Med. 1993;329:1615-1622.
7
8
% Patients With TIMI Grade 3 Flow
TIMI Grade 3 Flow – Pooled Data From Dose
Confirmation Phases of Recent Trials
100
Lytic alone
Combination
78
80
73
70
73
64
60
54
56
54
56
47
40
40
20
0
292
GUSTO-I
90 min
63 58
87 88
T14 t-PA
90 min
T14 r-PA
90 min
98 100
81 75
329 321
SPEED
INTRO-AMI
Pooled
60-90 min
60 min
60-90 min
SPEED: Results of Dose-Confirmation Phase
100
TIMI-2
TIMI-3
Patency (%)
80
28.7
21.6
60
54.9
40
47.5
20
n=109
n=115
r-PA 10+10 U
r-PA 5+5 U + Abx
0
The SPEED Study Group. Circulation. 2000;101:2788-2794.
• 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%
GUSTO-V: Study Design
ST , lytic eligible, < 6 h (n=16,588)
ASA
No Abciximab
Abciximab
2 x 10 U bolus (30’)
Full-dose r-PA
2 x 5 U bolus (30’)
Half-dose r-PA
Standard Heparin:
Low-dose Heparin:
5000 U bolus followed by
800 U/h (< 80 kg) or
1000 U/h ( 80 kg) infusion
60 U/kg bolus followed by
7 U/kg/h infusion
1º end point: mortality at 30 days
2º end point: clinical and safety events at 30 days
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
Primary End Point: 30-Day Mortality
% Mortality
6
5.9%
5.6%
4
P=.43 for superiority
Non-Inferiority RR 0.95
(95% CI, 0.84-1.08)
2
Std. Reteplase (n = 8260)
Abx +  Dose Reteplase (n = 8328)
0
0
5
10
15
20
Days
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
25
30
GUSTO-V: Noninferiority Analysis
Upper Boundary of 95% CI for Noninferiority
1.11
OR and 95% CI
Non-Inferiority RR 0.95
(95% CI, 0.84-1.08)
0.0
1.0
Abciximab +
Half-dose r-PA superior
Full-dose r-PA
superior
Adapted with permission from the GUSTO-V Investigators. Lancet.
2001;357:1905-1914.
2.0
A Comparison of the Outcomes With r-PA
Monotherapy in GUSTO-III vs GUSTO-V Trials
8
P<.001
7.4%
50
1.0
48%
0.9
7
5.9%
6
40
37%
0.91%
0.8
0.7
5
30
0.59%
0.6
4
0.5
20
3
0.4
0.3
2
10
0.2
1
0
P=.015
0.1
10,138
8,260
GUSTO III GUSTO V
Death
0
10,138
8,260
GUSTO III GUSTO V
Anterior MI
The GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
0
10,138
8,260
GUSTO III GUSTO V
ICH
GUSTO-V: Causes of Reinfarction
Myocardial Infarction (%)
4
P<.0001
3.5
r-PA
r-PA + Abx
3
2.7
2.3
2
1.7
1.6
1.2
1
0.5
0.2
0
Any
Q-wave
*Unblinded, unadjudicated
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
Enzymatic
Ischemic ST
Change*
Non-Intracranial Bleeding Through
Discharge/Day 7
30
% of Patients
25
24.6
r-PA
r-PA + Abx
20.0
20
15
13.7
11.4
10
5.7
10
4.0
3.5
0.5
1.1
1.8
0
Severe
Bleeding
Moderate
Bleeding
Mild
Bleeding
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
Any
Bleeding
Receiving
Transfusions
ICH by Age Group
% of Patients
3
r-PA (n=8260)
r-PA + Abx (n=8328)
P=.069*
2.1
2
P=.53
1.5
1.2
1
P=.27*
P=.66
0.4
0
1.1
0.5
0.3
0.4
24/6230 21/6193
25/2030 31/2135
37/7172 28/7179
12/1088 24/1149
 70 yrs
> 70 yrs
 75 yrs
> 75 yrs
*Significant treatment interaction for the age 75 dichotomy; P=.033.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
GUSTO-V: PCI Within 6 Hours (Urgent)
and Through Day 7
*
27.9
30
*
25.4
25
PCI (%)
20
Urgent
Through Day 7
15
10
*
8.6
*
5.6
5
0
r-PA
r-PA + Abx
*P<.0001.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
GUSTO-V: Event Rates in Those Requiring
Urgent PCI
Myocardial Infarction (%)
12
10
r-PA
r-PA + Abx
n=1173
9.6
9.0
8
6.7
6
5.4
4.8
4
2.8
2
0
Death
Repeat MI
Death Plus Repeat MI
Heartwire News. September 2, 2001. GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An
Alternative approach to MI?
GUSTO-V: Conclusions
• Compared with r-PA monotherapy, combination therapy
with
r-PA and abciximab resulted in
– A mortality rate that was not inferior to r-PA
monotherapy
– Fewer nonfatal reinfarctions (primarily a reduced
incidence
of recurrent ST elevation)
– A lower rate of urgent revascularization
– More noncerebral bleeding complications, transfusions,
and thrombocytopenia
– A higher rate of ICH in elderly patients over the age of
ASSENT-3: Rationale for Use of Enoxaparin
• TNK-tPA plus enoxaparin
– Favorable effects of LMWHs in recent small-scale
thrombolysis trials
– Higher late patency: HART-2
ASSENT-Plus
AMI-SK
– Less reocclusion:
HART-2
– Fewer reinfarctions: ASSENT-Plus
AMI-SK
Wilson, et al.
• ASSENT-3 is the first large-scale trial to test LMWH
ASSENT-3: Study Design
ST-Segment Elevation AMI (n=6095 patients)
150 to 325 mg ASA (daily)
Randomized
Full-dose TNK-tPA
Plus Enoxaparin
Half-dose TNK-tPA Full-dose TNK-tPA
Plus Abciximab
Plus WeightPlus Low-dose Heparin adjusted UFH
The ASSENT-3 Investigators. Lancet. 2001;358:605-613.
ASSENT-3: Primary End Points
• Primary Efficacy End Point: Composite of 30-day mortality
or
in-hospital reinfarction or in-hospital refractory ischemia.
• Primary Efficacy Plus Safety End Point: Composite of 30day mortality or in-hospital reinfarction or in-hospital
refractory ischemia plus in-hospital intracranial
haemorrhage or in-hospital major bleeding other than
intracranial.
% Risk of 30-Day D/MI/Ref Isch
ASSENT-3: 30-Day Mortality, Recurrent MI,
Refractory Ischemia
3-way P=.0001
20
P=.0009*
P=.0002*
15.4
15
11.4
11.1
TNK-tPA + Enox
TNK-tPA + Abx
10
5
0
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.
ASSENT-3: 30-Day Mortality, Recurrent MI,
Refractory Ischemia, Major Bleeding and ICH
3-way P=.0062
% Risk of 30-Day D/MI/
Ref Isch/Maj Bleed/ICH
20
P=.0146*
P=.0057*
15
13.8
14.2
TNK-tPA + Enox
TNK-tPA + Abx
17.0
10
5
0
TNK-tPA + UFH
*P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values
were P=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison.
Kaplan-Meier Curves
Primary Efficacy End Point
20
18
18
14
Enox*
12
Abx*
10
UFH
16
Probability (%)
Probability (%)
20
UFH
16
Primary Efficacy Plus
Safety End Point
8
6
4
Abx
14
Enox*
12
10
8
6
4
log-rank P=.0001
*vs UFH
2
0
log-rank P=.0062
*vs UFH + Abx
2
0
0
5
10
15
20
25
Days to death, reinfarction, or
refractory ischemia
30
0
5
10
15
20
25
30
Days to death, reinfarction, refractory
ischemia, ICH, or major bleeding
Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:605-613.
ASSENT-3: Primary Efficacy and Safety End Point of
Death, Reinfarction or Refractory Ischemia, ICH or
Major Bleeding in Patients >75 Years of Age
% Risk of 30-Day Efficacy
and Safety End Point
45
P=.001*
40
36.9
35
30
28.0
25.5
25
20
15
10
5
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
*There was a statistically significant interaction between treatment with abciximab and age such that
patients over the age of 75 had poorer outcomes with abciximab (P=.001).
ASSENT-3: Primary Efficacy and Safety End Point of
Death, Reinfarction or Refractory Ischemia, ICH or
Major Bleeding in Patients with Diabetes
% Risk of 30-Day Efficacy
and Safety End Point
30
P=.007*
25
22.3
20
16.5
15
13.9
10
5
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
*There was a statistically significant interaction between treatment with abciximab and diabetes, such that
diabetics had poorer outcomes with abciximab therapy (P=.0007).
ASSENT-3: 30-Day Mortality
% Risk of 30-Day Mortality
10
3-way P=.25
8
6.6
6
6.0
5.4
4
2
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
ASSENT-3: 30-Day Death or MI
% Risk of 30-Day Death or MI
10
3-way P=.0198
8
6.8
9.1
7.3
6
4
2
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
ASSENT-3: In-Hospital Recurrent MI
5
3-way P=.0009
% Risk of In-Hospital
Recurrent MI
4.2
4
3
2.7
2.2
2
1
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
ASSENT-3: In-Hospital Refractory Ischemia
% Risk of 30-Day
Refractory Ischemia
10
3-way P<.0001
8
6.5
6
4.6
4
3.2
2
0
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
ASSENT-3: Incidence of In-Hospital
Thrombocytopenia and Noncerebral Bleeding
Complications
Enox
(n=2040)
Any thrombocytopenia
Thrombocytopenia
<20,000 cells/µL
20,000 to 50,000 cells/µL
50,000 to <100,000 cells/µL
Abx
(n=2017)
1.2
3.2
UFH
(n=2038)
1.3
P-Value
3-way
<.0001
<.0001
0.1
0.2
0.9
0.5
0.6
2.0
0.2
0.2
1.0
Bleeding episodes
Total
Major
Minor
25.6*
3.0*
22.6*
39.7
4.3
35.4
21.1
2.2
18.8
<.0001
.0005
<.0001
Blood transfusion
3.4*
4.2
2.3
.0032
*While 3-way P-value is significant, Enox vs UFH comparison P=NS
ASSENT-3: In-Hospital Stroke Rates
Enox
Abx
UFH
(n=2040) (n=2017) (n=2038) P-Value
Total strokes
1.62
1.49
1.52
0.94
Intracranial hemorrhage
0.88
0.94
0.93
0.98
Ischemic stroke*
0.64
0.40
0.54
0.57
Hemorrhagic conversion 0.07
0.07
0.00
0.77
Unclassified
0.15
0.05
0.59
*Including hemorrhagic conversion
0.15
Patients Undergoing PCI: Mortality
8
ASSENT-3: In-Hospital PCI
GUSTO-V: Urgent PCI
7
6.7
Mortality (%)
6
5.4
5
4
3
3.7
2.7
2.5
2
1
0
TNK-tPA +
Enox
TNK-tPA +
Abx
TNK-tPA +
UFH
r-PA +
UFH
r-PA +
Abx
How Does Actual Weight Compare to
Estimated Weight?
Correlation Between Estimated and Actual Patient Weight in TIMI
10B
Actual Patient Weight (kg)
188.5
R2=0.93, P<.0001
40.5
36.4
Estimated Patient Weight (kg)
Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.
181
Weight-Based Dosing of Thrombolysis: How Well
Do We Estimate Weight? How Often Would This
Translate Into Errors With Administration of
Thrombolytic Drugs and Adverse Outcomes?
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
TNK-tPA + Abciximab Therapy
• “The results obtained with half-dose tenecteplase plus
abciximab are very similar to those with half-dose reteplase and
abciximab seen in GUSTO-V.”
• “In both trials, these benefits are obtained at the cost of a higher
rate
of major bleeding complications and blood transfusions.”
• “No benefit and perhaps even harm was observed in patients
above
75 years and in diabetics.”
• “Taken together they suggest that caution should be exercised
regarding the use of conjunctive therapy with abciximab in
elderly patients with an acute myocardial infarction treated with
a fibrinolytic
agent.”
The ASSENT-3
Investigators.
Lancet. 2001;358:605-613.
ASSENT-3: Study Group Conclusions Regarding
Enoxaparin
“In view of the present data and the ease of administration,
enoxaparin might be considered an attractive alternative
anticoagulant treatment when given in combination with
tenecteplase.”
The ASSENT-3 Investigators. Lancet. 2001;358:605-613.
ENTIRE TIMI-23: Study Design
ST  MI <6h (n=461)
ASA
Standard
Reperfusion:
Combination
Reperfusion:
Full-dose TNK-tPA
(0.53 mg/kg)
Half-dose TNK-tPA + Abx
(0.27 mg/kg)
UFH
ENOX
 UFH
 ENOX
60 U/kg bolus
12 U/kg/h
infusion
 36 h
varying doses
+/- IV bolus
Index Hosp ( 8
d)
40 U/kg bolus
7 U/kg/h
infusion
 36 h
varying doses
+/- IV bolus
Index Hosp ( 8
d)
Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.
Outstanding Issues
• Should enoxaparin replace UFH as the optimal antithrombin
agent for AMI?
• Will similar improvements in efficacy and safety occur if
enoxaparin is combined with a less fibrin-specific agent such
as r-PA?
• Will physicians accept the use of enoxaparin in selected
patients
with ST-elevation MI who may require rescue PCI?
• Will trials of TNK-tPA plus the small molecule GP IIb/IIIa
receptor inhibitors produce results similar to ASSENT-3?
• What is the optimal strategy for facilitated PCI?
Future Trials: Potential Downstream Targets
• Large embolii: Filters
• Small embolii (thrombii): Filters & GP IIb/IIIa inhibitors,
p-selectin inhibitors
• Vasoconstrictor release: GP IIb/IIIa inhibitors
• Spasm: Adenosine, Ca channel blockers, alpha blockers,
avoid over sizing with PCI, high pressure inflations,
serotonin inhibitors, endothelin inhibitors
• Endothelial & Myocardial swelling: Myocardial cooling,
Ca channel blockers, DHEA, Na / H pump inhibitors,
anti-inflammatory approaches
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
Conclusions (cont.)
Anticoagulants — Indirect Antithrombins —
UFH & LMWH
• Antithrombin therapy treats acute exacerbation via
short-term treatment
• UFH+ASA better than placebo or ASA alone in
reducing CVD/MI/RA
• LMWH has clinical advantages over UFH, and is a
useful agent early in treatment
Conclusions (cont.)
Anticoagulants — Direct Antithrombin - Hirudin
• Studied internationally in 29,000+ patients
• Neutralizes clot-bound and soluble fibrin; no allergic
reactions (lack of HIT)
• In acute MI, hirudin and UFH have equivalent effects
as adjunctive therapy to thrombolysis
• In PTCA, hirudin is associated with fewer cardiac
events compared to UFH
• In ACS, hirudin is superior to UFH:
– CVD/MI RRR 14% — 24%
– CVD/MI/RA RRR 19% — 22%
Conclusions (cont.)
Summary
• Direct thrombin inhibition offers benefits over indirect
thrombin inhibition for ACS
• Hirudin appears to be a safe, superior alternative
to UFH
• Longer treatment durations need to be assessed for
possible long-term benefits
• Combining a thrombin-specific inhibitor (eg, hirudin)
with a GP IIb/IIIa blocker may be an even more
effective antithrombotic therapy for ACS
Comparative Advantages of
Stress Echocardiography and Stress Radionuclide Perfusion Imaging in
Diagnosis of CAD
•
Advantages of Stress Echocardiography
1. Higher specificity
2. Versatility - more extensive evaluation of cardiac anatomy and function
3. Greater convenience / efficacy / availability
4. Lower cost
•
Advantages of Stress Perfusion Imaging
1. Higher technical success rate
2. Higher sensitivity - especially for single vessel coronary disease involving the left
circumflex
3. Better accuracy in evaluating possible ischemia when multiple resting LV wall
motion abnormalities are present
4. More extensive published data base - especially in evaluation of prognosis
Prognostic Markers in Exercise Testing
The Duke Treadmill Score (risk calculation)
The Duke treadmill score =
– exercise time in minutes on Bruce Protocol
– minus 5x the ST-segment deviation
(during or after exercise, in millimeters)
– 4x the angina index
(“0” if there is no angina, “1” if angina occurs, and
"2" if angina is the reason for stopping the test).
• works well for both inpatients and outpatients, and equally well for
men and women
N Engl J Med 1991;325:849-53
Survival According to Risk Groups Based on Duke Treadmill Score
4 -Year Annual
Risk Group (Score)
Total Survival
Low ( +5)
62%
Moderate (-10 to +4)
High (< -10)
34%
Mortality
99%
95%
4%
N Engl J Med 1991;325:849-53
0.25%
1.25%
79%
5.00%
Risk Stratification With Coronary Angiography
•
the extent and severity of coronary disease and LV dysfunction are the most
powerful clinical predictors of long-term outcome
– proximal coronary stenoses
– severe left main coronary artery stenosis
•
CASS registry of medically treated patients, the 12-year survival rate
Coronary arteries
Ejection fraction
normal coronary arteries 91%
one-vessel disease
two-vessel disease
three-vessel disease
50% to 100%
74%
35% to 49%
59%
<35%
40%
Circulation 1994;90:2645-57
73%
54%
21%
Risk Factors for
Coronary Artery Disease
•
Age: > 45 y/o male; > 55 y/o female; or post-menopausal female without estrogen
therapy
•
Male gender
•
Hypertension
•
Diabetes mellitus
•
Hypercholesterolemia/Hypertriglyceridemia
•
Smoking
•
Family history of early CAD
female age < 65; male age < 55
•
Past personal history of PVD or CVA
Risk Factors for
Coronary Artery Disease (con’t)
•
Left ventricular Hypertrophy
•
Cocaine/Ethanol Abuse
•
Obesity
•
Sedentary Lifestyle
•
Oral contraceptives
•
Homocysteine elevation
•
Fibrinogen, C-reactive protein, Lp (a)
Guidelines to Reduce Risk For Patients With
Coronary Disease and other vascular disease
 Cessation of smoking






Lipid Management Goals
Primary Goal: LDL < 100 mg/dl
Secondary: HDL > 35 mg/dl TG < 150 mg/dl
Physical activity: 30 minutes 3-4 times per week
Weight management
Antiplatelet/anticoagulants:ASA 80 to 325 mg/day
(or clopidogrel 75m/day)
 ACE inhibitors (post-MI for LVD)
 Beta blockers for high-risk patients post-MI
 Blood pressure control: goal < 130/85 mm Hg
Adapted from Smith, Circulation 1995;92:3
Medical Therapy For Patients
with CAD or Other Vascular Disease
Risk Reduction
•
ASA
20-30%
•
Beta Blockers
20-35%
•
ACE inhibitors
•
Statins
22-25%
25-42%
The four medications every atherosclerosis patient should be treated with,
unless contraindications exist and are documented
Adapted from the UCLA CHAMP Guidelines 1994
Protocol Design
TIMI IIIA
391 Patients with Unstable Angina / NQWMI
IV Heparin, (ASA), Beta-blockers,
Nitrates, Ca++ blockers
Baseline Angio
Angio Exclusion:
no CAD or LMain
Randomize
t-PA
0.8 mg/kg over 90 mins
Primary Endpoint:
Death, MI,
Positive ETT 6 weeks
Placebo
Angio 18-36 hrs
Follow-up 6 weeks
Circulation 1993;87:38-52
Primary Results
TIMI IIIA
Effects of tPA on Coronary Lesions
BASELINE ANGIORAPHY:
Apparent thrombus
35%
ANGIORAPHY AFTER tPA:
No thrombus
35%
Possible thrombus
30%
Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo
TIMI IIIA Investigators. Circulation 1993;87:38-5
Protocol Design
TIMI IIIB
1473 Patients with Unstable Angina / NQWMI
ASA, IV Heparin, Beta-blockers,
Nitrates, Ca++ blockers
Randomize
Early Invasive:
Cath 18-48 h
PTCA/CABG prn
2x2 Factorial:
t-PA vs. Placebo
1o Endpoint Inv-Cons:
Death, MI,
Positive ETT - 6 weeks
ETT 6 weeks
Circulation 1994;89:1545-56
Follow-up 1 year
Early
Conservative:
ST Holter, ETT
Thallium
Cath/PTCA if
+ischemia
1o Endpoint t-PA:
Death, MI, Rec Isch,
+ ETT, Thallium
or ST Holter
Primary Results
TIMI IIIBtPA vs. Placebo in Non-ST
Elevation ACS
Composite Endpoint
80
12
70
60
Death or MI
54.2
55.5
10
0.8
40
0.7
8.8
8
50
0.6
6.2
6
30
ICH
0.55
0.5
0.4
0.3
4
20
0.2
2
10
0
0.1
0
tPA
Placebo
P = NS
0
0
tPA
Placebo
P = 0.05
tPA
Placebo
P = 0.05
TIMI IIIB Investigators. Circulation 1994;89:154556
Primary Results
TIMI IIIB
Early Invasive vs. Conservative Strategy
Events at 42d
No. Pts
Death (%)
MI (%)
D/MI/+ETT (%)
Rehosp Angina (%)
D/MI/Rehosp (%)
LOS (days)
# Days rehosp
Invasive Conservative p value
740
733
2.4
2.5
NS
5.1
5.7
NS
16.2
18.1
NS
7.8
15
10.2
365
14.1
22
10.9
930
<0.001
0.007
<0.001
<0.001
TIMI IIIB Investigators. Circulation 1994;89:154556
TIMI III REGISTRY
Protocol Design
• All consecutive patients admitted with unstable angina were
screened.
• Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable
pattern: At rest, accelerating, post MI
• Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for
revascularization procedure
• Patients in specific subgroups defined by gender, race and age were
randomly selected for detailed evaluation and follow-up at 6 weeks
and 1 year.
Risk Stratification
TIMI III REGISTRY
Admission ECG as a prognostic indicator
_ >0.1 mV LBBB
ST deviation
Tw change No ECG changes
22.9
25
20
Death or MI
15
11
10
5
6.8
6.6
2.6
0.8 1.6 1.6
3.6
8.2
3.7 3.7
0
In-Hospital
6 Weeks
1 Year
Stone PH, TIMI III Registry Study Group. JAMA 1996;275:11041112.
TIMI IIIB
Risk Stratification
cTnI to Predict Risk of Mortality in ACS
All Patients
Enrolled 0-6 hrs
No CKMB Elev
P<0.001
All Patients
Enrolled 6-24 hrs
P <0.05
No CKMB Elev
P<0.001
All Patients
Enrolled 0-24 hrs
P <0.05
No CKMB Elev
0
1
2
3
4
5
TnI < 0.4 ng/ml
TnI > 0.4 ng/ml
Mortality at 42 Days (%)
Antman et al. NEJM 1996; 335:1342-9
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