Chest Pain Evaluation

Content.
• Brief overview.
• Risk factors
• Enzymes
• Cases
• Trial
 Acute Coronary Syndromes

Noncardiac
Unstable angina
Variant
Progressive
NQWMI angina
Rest New onset angina
Post MI Prior CABG/PTCA
Prior MI
 What time of day is it?
Non-ST Segment Elevation - Acute
Coronary Syndromes
A Spectrum

Rest angina “Small” “Large”

Rule-out MI Infarctions Infarctions

NQWMI QWMI NQWMI

U angina

CPK/ troponin
rise
 Clinical Trials HowA big
do we
pilemake
of
sensespaghetti
of this mess ?
FRISC ESSENCE FRIC TIMI 11
EPIC HIT III
PARADIGM RAPPORT
TIMI 12
PROLOG PRISM
EPILOG
ERASER HERO
GUSTO II TIMI 14
PURSUIT PARAGON IMPACT AMI
HELVETICA
EPI-STENT CAPTURE TIMI 9
MINT
RESTORE SPEED TAMI 8 PRISM-PLUS
REDUCE AMI IMPACT II
ORBIT IMPACT SOAR
How do you keep up with the
stats/subset argument?
• Should the first question be

• To cath or not to cath?

• If so now or tomorrow?
• Then work backwards rather than work
upwards through an algorithm
 Common Questions
• Who to admit: role of delay/enzymes?
• Risk stratification: what current rules?
• How aggressive with unstable angina?
• How aggressive with PTCA in MI
• What effect does age make in each group?
• Why does it sometimes appear to not make
sense?
 ATTACK the Clot or the
Lesion?
The Evolution of Atherosclerosis
Foam Fatty Intermediate Fibrous Complicated
Cells Streak Lesion Atheroma Plaque Lesion/Rupture

Endothelial Dysfunction

From
From 1st
1st Decade
Decade From
From 3rd
3rd Decade
Decade From
From 4th
4th Decade
Decade

Growth
Growth Mainly
Mainly by
by Lipid
Lipid Accumulation
Accumulation Smooth
Smooth Muscle
Muscle Throm
Thrombosis,
bosis,
&& Collagen
Collagen Hematoma
Hematoma
Adapted From Stary HC et al. Circulation
Circulation.. 1995;92:1355-1374
 A paradigm issue
• Is it innocent till proven guilty
• OR
• Guilty till proven innocent.
 Acute chest pain ::::inputs

C h e s t p a i n

1 0 % S T c h a n2 g0 e% s A M 3I 0 % U n s t a b l 4e 0 a % n g Ni no a A
p r o b n o n c
 Acute chest pain ::::outcomes

• One of 10 gets lysed or “cathed”

• The other 9 need risk stratification.

Types of Chest pain.

Traumatic

Nontraumatic.
Not Traumatic Chest Pain
• Most Challenging

• May be dramatically ill on presentation.

• May be completely well.

• At serious risk for Sudden cardiac death

Seriously Compromised Patients
• Easily Recognized.
• Dx usually made from
Hx
Clinical Examination
ECG
CXR
ABG’s.
Falling into this category are
• ACS Aortic Dissection
• Massive PE Pneumonia
• Oesophageal Rupture

• Pericarditis with a tamponade.

Even more challenging are
• Pts with less severe symptoms
• May have resolved @ time of examination
• What to do with these pts?
• Need to provide a cost-effective care?
• Pts and relative expectations
• Missing a Dx is not acceptable.
Why is the aetiology of CP often difficult to
determine in the ED?
• Varioius disease processes in a variety of organs
may result in CP.
• Severity of CP is often unrelated to its life-
threatening potential.
• Location of the CP by the patient may not
correspond with its source
• Clinical Exam,Lab studies,and radiology may be
nondiagnostic.
Is the location of pain diagnostic of its
aetiology?
• No.

• Somatic fibres
Numerous
Enter @ single level(spinal cord)
Results in sharp localized pain.
• Visceral Afferents
Internal organs
Less numerous
Enter (SC) @ multiple levels
Visceral Pain
Dull
Aching
Poorly localized
Differential Dx of Non traumatic CP.
• Cardiac Cause
Stable angina
Unstable angina
Variant angina
AMI
Pericarditis
Valvular Diseases AS
MVP
• Vascular Causes
Aortic Dissection
PE
PH’Tension
• Pulmonary Causes
Pleural irritations
Infections
Inflammation
Infiltrations.
• Pulmonary Causes(cont…)
Barotrauma
Pneumothorax/Mediastinum.
Tracheobronchitis.
Musculoskeletal.
Costochordritis
Muscle strain
Cervial Thoracic spine problem
• Gastrointestinal Causes
Reflux
Mallory Weiss tear
Biliary Colic
Pancreatitis
Dyspepsia
Miscellaneous Causes
Herpes Zoster
Chest Wall Tumors.
What is the safest initial approach to pts
presenting with CP?.
• Approach with assumption of a life-
threatening aetiology.
• Before any Diagnostic studies
Suplemental O2
IV access
ECG
How do I begin to assess the Pt with CP?
• An accurate + targeted Hx (Most important
component)
@ triage
RMO

• Factors to consider include

The onset
Quality
Assessment of CP……….
Location

patter n of radiation

Duration of pain

Associated symptoms.
Precipitating factors
Exertion
Movement
Inspiration
Relieving Factors.
Rest
GTN
Antacids
Body position
Major Risk Factors with IHD?.
• Family Hx,

• Cigarette smoking,

• HBP,

• Hypercholesterolemia ,

• Diabetes Mellitus.

• Age >40.
Major Risk Factors(cont……)
• Male Sex,

• Important in establishing the Dx of angina

• All except Family Hx can be modified to

reduce the chances of developing CAD.

• Chronic cocaine use in the younger pts.

Is Radiation of pain significant?.
• Suggestive but not diagnostic.
• Visceral pain including
Aortic
Oesophageal
Gastric
Pulmonary.
May also present with radiation of Pain to the
neck,shoulder and arm.
How does the patient’s appearance
correlate with the origin of CP?.

• Catastrophic illnesses often results in

Anxiety

Diaphoresis

ill looking appearance.

Are Vital Signs Helpful?.
• May provide valuable information.
BP
• Diff between the upper extremities
(Dissecting Aneurysm)
Tachyponea
Hypoxia of PE
Hypoxia of Pneumonia
2nd to pain.
Vital sign (cont…..)

Elevated Temperature
Inflammatory(Pericarditis)
Infectious process(Pneumonia).
Are there any physical examination finding which
may help differentiate among the causes of acute
CP?.

• Isolated physical findings are rarely

diagnostic of the origin of CP.
• When used in context with the Hx it may be
extremely valuable.
Cont…..
• Localized tender ness
(?Musculoskeletal).
beware 5-10% of pts with CP reproduced
by palpation have IHD.
• Auscultation (New murmurs)
Murmur of AI Aortic Dissection
Murmur of MI Inf MI (papillary dys )
Pericardial Rub ?Pericarditis.
How is the ECG helpful in IHD?.
• Provides documentary evidence of cardiac
ischemia/infarction when positive.
• Normal in ~ 50% initially who are later Dx as
having an AMI.
• Necessary to fulfil the criterion for the
administration of thrombolytic agents.
ST elevation >1mm in limb leads

ST elevation >2mm in Anterior leads.

ECG in IHD cont………
• Comparison with the old ECG may reveal subtle
but significant changes.
• A normal ECG does not exclude an AMI
• Pts without evidence of
AMI LBBB
IschemiaLVH
ECG cont…...
• Have minimal risk of developing life-threatening
complications and may be observed in a step-
down unit.
• Efforts to improve the Sens/Specificity for the
detection of AMI/ACI, have included 15-lead
ECG
Stand 12 + V4r,V8,V9.
How useful is the resting ECG in
evaluating pts with angina?
• Obtain in all pts with chest discomfort.
• In pts with chronic stable angina it is N in
33%
• The presence of LBBB in pts with angina is
often ass with significant LV dysfunction
and may indicate multivessel CAD.
• The presence of a Q-wave is usually a
specific but insensitive indicator of MI.
Are cardiac enzymes useful in the
evaluation of CP in the ED?
• Yes.
• Assay for the enzymatic breakdown products
2nd ischaemic myocardial cellular damage.
• Early serum markers include
Myoglobin
CK and its isoenzyme band
Troponin T,I.
Cardiac myosin light chains
Serum Markers cont,,,,,,,,,
• All reflect myocardial necrosis that has
already occurred.
• Normal levels do not exclude ischemia but
that significant damage has not yet been
delivered to the bloodstream.
• If serum markers are +ve Myocardial cell
damage can be “ruled in”
Serum Markers cont……
• If -ve Myocardial ischemia cannot be “ruled
out”
• Recently newer assays with earlier serum
peaks have generated interest in “short-stay
protocols” to rule out MI
• Studies have suggested if
1.Initial clinical suspicion is low for ischemia
and
2 Normal serial ECG’s and enzymes
Serum markers cont……
• These pts may be discharged safely from the
ED leading to
Substantial cost savings
(not standard practice yet!)

Myoglobin
• Elevation within 1hr post AMI
• Peaks within 4-12hrs
• Elevated in ~ 60% pts with AMI @ 1hr post
presentation.
• Does not detect UAP+
• Elevated in ~ 100% within 3hrs of AMI.

Not specific for Myocardial cell damage

Skeletal muscle injury
Heavy alcohol use
Renal failure
Shock states.
Various other clinical states.
CK-MB
• Specific for AMI
• % of pts with AMI and +ve results
increases over time from 1/3 @ presentation
to 90% @ 4hrs.
• The utility of the assay in ED as a one-time
test is limited because levels do not
significantly rise until 4-6hrs.
• Use of multipleCK-MB tests over several
hrs has very good diagnostic performance
for AMI.

• Despite the growing CPU , are there

adequate resources to observe pts for
several hrs in ED before making disposition
decisions.? I think not!!!!!
Proteins of Troponin Complex.
• Complex is located on the thin film on the
contractile apparatus.
Striated Muscle
Skeletal Muscle.
• 3 Subunits
Troponin-T (TnT:tropomyosin-binding
subunit)
Cardiac enzymes cont……….
Troponin-I (TnI:The actomyosin-adenosine
triphosphate-inhibiting subunit)

Troponin-C (TnC:Calcium-binding subunit)

• A +ve TnT was found to be ~ 6X as predictive of

adverse events as a -ve result.(AEM jan 98)
• TnC+ TnT are found in both muscle.
• TnI is said to be specific for myocardial
fibers,making it highly specific and
sensitive to myocardial injury.
• ? valuable tool for the ED in identifying
which pts might benefit from a more
aggressive Tx approach and a higher level
of inpt’ care.
• Cardiac Troponin is an independent
prognostic marker of severity of UAP.
• Troponin levels > 0.4mg/ml are predictive
of increased 6wk mortality (Lindal et
al.Circ 1995).
• Performed at the bedside,and completed in
20 mins,useful for rapid identification in
ED setting(Antman et al JAMA 1995)
 ENZYMES.
Most labs now only doing Troponin 1 (huge topic,
Quality Control Issue).

BUT not good early:

- Rise at 3-6
- Peak at 14-18
- Stays for days.

CAN WE USE IN ED TO SEND HOME? NO

Cases.
45yr male patient with Chest pain
• Presents to your Ed.
• What are you going to do???
 At triage.
• Assess and risk stratify.
• Pain description
• Age
• Sex
• CAD
• Cocaine abuse
• Risk factors for CAD.
• 2 hr of pleuritic chest pain and SOB.

• Ass with cough productive of sputum

• Rigors for the last 2 days.

• Clinically has a RLL Pneumonia.

• CXR shows patchy consolidation in RLL
• Needs admission for IV antibiotics.
 65 yr male with chest pain.
• Chest pain for 1 hr “like someone squeezing me”
• No associated symptoms of
sweating
SOB
Dizziness
• Pain radiated to the neck and L arm
• Has a +ve family history (father died of MI)
• Smokes 23/day for 40 yrs.
• What is your diagnosis.?
• What are you going to do ?
 Is this ACS?
• Yes.
• What now?
• Triage to a resuscitation bay .
• Needs what?
O2
IV access for relevant bloods
12-lead ECG.
Aspirin (clopidogrel )
 Consider
• B-blockers
• Nitroglycerin
• Morphine sulfate.
• What are the possible pathways of this patient?

It depends what the ECG shows.

1.New ST-segment depression or t-wave inversion.

2.St-segment elevation or new LBBB.
3.Normal ECG or No ECG changes.
 If no ECG changes or N ECG what then?
Risk Stratify.
• Complete history and physical
Consider
• Serial ECGs or continuous segment monitoring
• Second set of cardiac markers (at ≥ 6 hrs after chest
pain.)
3. If first troponin obtained at < 6 hrs, obtain 2nd set
between 6-12hrs.
4. 2-D Echogram
Observation where?
• ED
• Chest pain unit
• CCU

Pain relief (initiate or intensify)

b-Blockers
Nitroglycerin
Morphine Sulfate.
 Re-evaluate pts for High risk Status
According to the following criteria:
• History
Presence of chest pain
2 or > episodes of resting angina during
the previous 24hrs.
History of 3 or more cardiac risk factors
Diabetes
Smoking
Elevated LDL-cholesterol
Known CAD (documented stenosis 50% and
> in one major coronary artery)
Physical examination
• Age > 65 and over.
• CCF

ECG findings of
New St-segment deviation of 0.5mm or> in
limb and or precordial leads.
New pathological Q waves.
Sustained VT.

Markers
• Significant elevation.
 If all of the above are Negative
• Low risk
• Treat the suspected aetiology
• Consider Stress Testing to provoke
ischemia (prior to discharge or as an OPD)
• Follow up as needed.
 If Positive for high risk
• Enoxaparin (preferred) or unfractionated
heparin.

• Why Enoxaparin??
Why Use Low Molecular Wt Heparin (LMWH)?.
• Unlike UFH, enoxaparin has
1.More predictable kinetics,
2.Is less protein-bound,
3.Has less potential for platelet activation,
4.Requires no monitoring;

• This is a combination of benefits that provides

a strong rationale for achieving potentially
better outcomes when this LMWH is given in
combination with fibrinolytic agents.
 Superior outcomes with
Enoxaparin
• The superior outcomes with enoxaparin vs. UFH across
the entire spectrum of acute coronary syndromes
(ACS), including, most recently, its value in ST-
elevation MI as reported in ASSENT-3, have elevated
this antithrombin agent to a prominent position
among pharmacological modalities used to
manage acute coronary ischemia.
 LMWHs obtain antithrombotic levels
within ? Time.

• 30mins.

• They are readily absorbed from the SC tissue

• Rapidly distributed to most organs and tissues

What is the bioavailability of the
LMWH vr UFH
• 90%vr 30%
• Primarily related to heparin’s increased
binding to plasma proteins, macrophages,
and enothelial cells.
 65 yr female.
• Crushing Chest pain for 1hr.
• Associated with Sweating and SOB
• Pain radiated to the neck.
• +ve family history mother died at 60 of MI.
• Smoker
• No other risk factors.
• What are you going to do?
• 12 lead ECG within 10mins of arrival
• IV access
• O2
• Monitoring
• Aspirin (clopidogrel)
• Consider
Cardiac Markers
b-Blockers
Nitroglycerin
Morphine sulfate.
 ECG shows.
• New ST-segment Depression
• New T wave inversion.
• Initial Cardiac enzymes raised.
• What is your DX??
• Non ST –elevation MI
• Now how are you going to treat her and
why?
• B-Blocker
• Enoxaparin
• Nitroglycerin
• Morphine Sulfate.

This lead on to 2 stratergies.

1.Dominant Strategy.
• Recommend early cardiac catherization (<
48hrs)
• Clopidogrel pretreatment.
 If Catherization is Normal
• Discharge and follow up as needed.

• If the cath is abnormal

• Proceed to Coronary intervention.What type?
• Also use GP IIb/IIIa inhibitor (abciximab)
• Why use the GP IIb/IIIa inhibitors??
 Glycoprotein GP IIb/IIIa
inhibitors
• The results have been mixed in
patients not requiring procedural
coronary intervention (PCI)
• Have been very favourable in
patients requiring PCI, especially in
the case of coronary stent
insertion.
 phase III-(GUSTO)-V trial
• Demonstrated a reduction in ischemic complications of
AMI with half-dose rPA and abciximab, as compared
with full-dose reteplase.
• It failed to show a significant reduction in 30-day
mortality, + there was a significant increase in non-
cerebral bleeding complications;
• This offset potential benefits and dampened
enthusiasm for an imminent paradigm shift that
routinely would include abciximab as a workhorse
drug in fibrinolytic protocols in the absence of
PCI.
 PCI
• Includes (PTCA) or coronary stenting, has
many theoretical and practical advantages
over fibrinolysis and is becoming the preferred
strategy for most patients with AMI.

1.There is a larger patient eligibility pool for PCI

2.A lower risk of intracranial bleeding
3.A significantly higher initial reperfusion rate.

• This strategy always affords earlier definition

of coronary artery anatomy and the ability to
risk stratify patients, thereby permitting rapid
triage to surgical intervention when indicated.
 PTCA
Thrombolytic
• Few exclusions
• Immediately available • Very reasonable outcome
• No operator expertise • Better initial flow
• Proven track record • Fewer bleeding complications
• Definition of anatomy
• Many exclusions
• More frequent bleeding
complications
• Not immediately available
• Operator expertise
 What is the optimal approach for
establishing coronary reperfusion after
myocardial infarction?
Depends on a number of clinical factors,
1. Patient eligibility for specific interventions (medical vs
procedural) based on risk stratification;
2. Adherence to risk-stratification protocols;
3. Availability of institutional resources for performing
interventional techniques;
4. Availability of cardiologists with sufficient experience in
transcutaneous coronary reperfusion techniques;
5. The ability to provide prompt patient transfer to another
hospital for those who may require PCI
6. The presence of exclusionary and inclusionary factors
that determine patient eligibility for fibrinolysis.
 Alternative Strategy (NQWMI)
• Medical management
• Consider clopidogrel

Admit and monitor pt for

Recurrent CP
Haemodynamic instability
New ECG
CHF
Dysrhythmias

• If any of the above will need to progress to the Dominant strategy.

• If none of the above
• ASSESS the LV function
• If >40% Proceed to a stress testing
If N →home
If abnormal → angio.
• If < 40% for angiogram.
 34 yr male
• 1hr history of crushing chest pain
• Radiation to neck and arms
• Associated with SOB and sweating
• No risk factors.
• What are you going to DO??
• Risk stratify at triage desk accordingly to
Pain description
Age
Sex
CAD Hx
Cocaine
risk factory for CAD.
 ECG shows.
• ST- Segment elevation in the anterior leads
of V2,V3, And V4.
• Or a new LBBB.
• What is your Tx.???
 Treat with
• B-Blockers
• Nitroglycerin
• Morphine Sulfate

• If Pain <12 hrs need to go to the dominant

strategy
• Need to find out if your institution is
capable of performing PCI
• Recommended catheterization followed by
PCI or CABG as clinically indicated
• Recommended clopidogrel pretreatment
• Recommended abciximab plus Enoxaparin
or UFH.

Door to balloon time

need to be <90 mins.
If institutions not able to perform
PCI
• What would you do???
• Fibrinolysis
• Preferred anticoagulant Enoxaparin plus
Reteplase
or
Tenecteplase
Door to needle time needs to
be <30mins.
Clinical evidence of reperfusion?
• Chest pain and ECG resolution.
• If yes continue medical management.

• If NO.
• Consider cardiac catheterization.
Fibrinolytic Therapy: The Current
Landscape

• In appropriately selected patients with AMI, early

administration of fibrinolytic agents reduces
mortality and is associated with improved short-
and long-term clinical outcomes.
1. Prompt restoration of patency in the infarct-related artery
reduces infarct size and minimises the extent of myocardial
damage,
2. Preserves left ventricular function,
3. Reduces morbidity,
4. Prolongs survival.
 Compared to standard therapy
• Fibrinolysis is associated with a 21% reduction in 30-day mortality.
• However, these agents also are associated with intracranial
hemorrhage in about 0.5-0.9% of patients.
• In addition, only 30-60% of patients achieve TIMI 3 (normal) flow
in the affected epicardial artery within 90 minutes.
• Because of these drawbacks, safer and more effective fibrinolytic
therapies have been developed through bioengineering techniques
on the tPA molecule.
• In addition, the role of combination therapy with
adjunctive agents, such as enoxaparin and GP
IIb/IIIa inhibitors, is emerging.
 From an outcome-effectiveness
perspective
• It should be stressed that mortality is affected by factors
other than epicardial vessel flow.
• In this regard, reperfusion at the tissue level may
be a critical factor in myocardial salvage, and this
does not necessarily correlate with epicardial vessel flow.
• Patients with documented TIMI 3 epicardial flow but poor
TIMI myocardial perfusion (TMP) grades (TMP 0 or 1) had
a higher mortality rate (5.4%) than those patients with
adequate (TMP grade 2 flow) or complete tissue
perfusion (TMP grade 3 flow), 2.9% and 0.7%,
respectively.
 Ideal fibrinolytic agent

• Rapid lysis
• Enhances tissue-level perfusion
• Reduces intracranial and systemic hemorrhage
• Has a long half-life enabling single-bolus
administration
• Has no antigenicity
• Has a low reocclusion rate.
• Enhanced fibrin specificity also is desirable
because it permits preferential activation of
fibrin-bound plasminogen at the clot surface
• This has the potential to increase
patency and produce higher initial
patency rates, and may be
associated with fewer bleeding
complications.
• Greater fibrin specificity also decreases
activation of circulating plasminogen
and degradation of fibrinogen, resulting
in less bleeding and reducing the need
for transfusion.
 Candidacy for Fibrinolysis—patient
Screening, Identification, and
Stratification

• Optimizing outcomes in patients with ACS

requires matching patients with
strategies that will produce the best results
in specific clinical subgroups.
• Identifying those patients who represent ideal
candidates for fibrinolysis, and who are likely
to have outcomes at least as favourable as
they would with procedural interventions, has
become an area of intense focus among
cardiologists and emergency physicians.
• Risk-stratify patients according to whom will
benefit most from either pharmacology or
procedure-mediated reperfusion.
• It has been difficult to generate a
deterministic patient selection process that
will guarantee an optimal outcome for each
individual case.
• TIMI risk factor analysis has emerged as one
of the most widely accepted approaches for
identifying patients who will likely benefit
from specific strategies.
 TIMI Risk Factor Analysis
1) presence of chest pain;
2) significant elevation of cardiac markers
3) history of three or more cardiac risk
factors (i.e., diabetes, smoking,
elevated LDL-cholesterol, etc.)
4) age 65 or older;
TIMI 9B Risk Stratification
Prediction of Mortality at 30 Days

% Pts: 26% 37% 24% 10% 3%

Hillis et al. TIMI 2 25 22.3

Mortality - 30 Days (%)

• Age > 70, 20
• Prior MI P<0.001 16
• Anterior MI, 15
• Atrial fibrillation
10 7.4
• Rales
• Hypotensionand  HR 5
1.6
2.9
• Female gender
0
• Diabetes
0 1 2 3 >4
Num ber Risk Factors

Canno n CP et al. JACC 1999;33(

Suppl. A):396A.
5) known coronary artery disease (CAD),
defined as documented 50% or greater
stenosis in at least one major coronary
artery;
6) prior chronic aspirin intake for CAD
prevention;
7) two or more episodes of resting angina
during the 24 hours prior to presentation.
8) new ST-segment deviation of 0.5 mm or
greater in limb and/or precordial leads.
 Patient Age
• In general, published trials do not provide
evidence to support withholding fibrinolytic
therapy on the basis of a patient’s age alone.
• patients older than age 75 have a higher
incidence of hemorrhagic stroke than younger
patients.
• Moreover, the recent GUSTO-V trial suggested
inferior outcomes when abciximab was
combined with UFH and TNK-tPA in patients
older than age 75
 Time from Chest Pain Onset,
Therapeutic Window.

• The generally accepted therapeutic window for

administration of a fibrinolytic agent after the onset
of ST-segment elevation AMI is 12 hours.
• The earlier the treatment is initiated, the greater the
likelihood that the patient will experience a good
outcome.
• This is the case in patients within the first six hours
of AMI.
• Delayed administration (i.e., those occurring
between six and 12 hours after AMI onset) also
confers benefit, although of a lesser magnitude.
 Stroke.
• A history of previous stroke or transient
ischemic attack (TIA) is a major risk factor
for hemorrhagic stroke after treatment
with fibrinolytic therapy.
• A history of previous ischemic stroke
should remain a strong relative
contraindication to fibrinolytic therapy.
• A history of previous hemorrhagic stroke
should remain an absolute
contraindication.
 Recent Surgery and
Trauma.
• Recent surgery or trauma is considered a relative
contraindication to fibrinolytic therapy.
• However, the term recent has been variably
interpreted in fibrinolytic therapy trials.
• GISSI-1 trial, patients were excluded if they had
surgery or trauma within the previous 10 days.
• In the Anglo-Scandinavian Study of Early
Thrombolysis (ASSET) trial, patients were
excluded for surgery or trauma within the
previous six weeks.
 Elevated Blood Pressure.
• Current evidence indicates that patients
with a history of chronic hypertension
should not be excluded from fibrinolytic
therapy if their blood pressure is under
control at the time of presentation or if
it can be predictably lowered to
acceptable levels using standard
therapy for ischemic chest pain.
• In this regard, the admission blood
pressure also is an important
indicator of intracerebral
haemorrhage risk.
 Hypertension.
• A persistent blood pressure greater
than 200/120 mmHg generally is
considered an absolute
contraindication to fibrinolytic
therapy
• The benefit of fibrinolytic therapy in
patients with hypotension remains
controversial.
• The GISSI-1 and GISSI-2 trials
show no apparent reduction of
mortality rate with fibrinolytic
therapy among patients classified in
either Killip class III or IV.
 Cardiogenic Shock
• Patients with AMI who present with cardiogenic
shock, which occurs in up to 10% of cases,
demand special attention because this
population has a mortality rate of almost 80%.
• Fibrinolysis is not effective in this subgroup of
AMI patients, most likely due to a significantly
lower coronary perfusion pressure; in the shock
state, it is felt that the occlusive thrombus is
not adequately exposed to the fibrinolytic
agent, which may account for the clinical failure
of the drug
 Menstrual Bleeding
• Previously, there has been concern regarding whether
menstruating women with AMI should be considered
candidates for fibrinolytic therapy.
• Because natural estrogen is cardioprotective, there
has been little experience with fibrinolysis among
premenopausal women.
• Significant adverse effects, however, have not been
reported by clinicians who administer fibrinolytic
therapy to such patients
• Gynecologists indicate that any
excessive vaginal bleeding that may
occur after receiving fibrinolytic therapy
should be readily controllable by
vaginal packing and, therefore, can be
considered a compressible site of
bleeding.
 The Electrocardiogram.
• Combined with the patient’s history and physical
examination, the 12-lead ECG is the key determinant of
eligibility for fibrinolysis.
ST-segment elevation
1 mm or more in two or more anatomically contiguous
standard limb leads and 2 mm or more elevation in two or
more contiguous precordial leads;
New or presumed new left bundle-branch block (LBBB).
• No evidence of benefit from fibrinolytic therapy is found in
patients with ischemic chest pain who lack either appropriate
ST-segment elevation or the new development of LBBB
• In patients with AMI, new-onset
LBBB is a clinical marker for a
significantly worse prognosis in
terms of higher mortality, lower
left ventricular ejection fraction,
and increased incidence of
cardiovascular complications
 ST elevation “ on arrival”
• No of lives saved/1000
• Strepto 26 tPA 36
• Newer agents NO improvement.
• Probably no further room to improve lysis
drugs.
Concept now to add and mix
• GP11b 111a + LMWH+ thrombin inhibitors+
P inhibitors
eg 1/2 dose rPA and axicimab (Gusto5)
• The current evidence strongly indicates that
fibrinolytic therapy should not be used
routinely in patients with ST-segment
depression only on the 12-lead ECG.
• The mortality rate actually may be increased by
administration of fibrinolytics in this patient
subgroup.
• TIMI-3 trial demonstrated a significant difference in
outcome in fibrinolytic-treated patients with only
ST-segment depression: 7.4% incidence of death
compared with 4.9% in the placebo group.
• FTT Collaborative Group meta-analysis,
demonstrated that the mortality rate among
patients with ST-segment depression who received
fibrinolytic therapy is 15.2%, compared with 13.8%
among controls.
 Recent Cardiopulmonary
Resuscitation (CPR).
• CPR is not a contraindication to fibrinolytic therapy
unless CPR has been prolonged (> 10 minutes) or
extensive chest trauma from manual compression is
evident.
• Although the in-hospital mortality rate is higher in AMI
patients who experience cardiac arrest and then receive
ED-based fibrinolytic agents, no difference is found in
the rates of bleeding complications. No hemothorax or
cardiac tamponade occurred in those cardiac arrest
patients receiving fibrinolytics.
Role Models.
 Low Molecular Weight Heparin
(Enoxaparin)— A Central Role in Fibrinolytic
Regimens

• The most important advance in fibrinolysis-

mediated management of AMI is the emerging,
evidence-based support defining a pivotal role
for enoxaparin as part of a TNK-tPA based,
fibrinolytic regimen.
• In this regard, the recently published ASSENT-3
trial was designed to compare the effectiveness
and safety of enoxaparin vs. UFH as part of a
full-dose TNK-tPA regimen
• The investigators concluded that the TNK-tPA
plus enoxaparin or abciximab regimens
reduced the frequency of ischemic
complications in AMI, producing an overall
relative reduction in primary adverse end
points of about 26% in the enoxaparin-TNK-
tPA and abciximab groups as compared to the
UFH group.
• However, in light of its ease of administration,
better safety profile, and lower cost as
compared to the abciximab-UFH-TNK-tPA
combination, the enoxaparin-TNK-tPA arm
emerged as the most attractive reperfusion
regimen.
• Because of superior clinical
outcomes as compared with UFH in
specific patient subgroups,
enoxaparin should be considered
the anticoagulant of choice for a
broad spectrum of patients with
AMI, whether treated with
fibrinolytic regimens and/or GP
IIb/IIIa antagonists, and also in
patients without ST-elevation
treated with PCI.
 Coronary Stenting.
• Support for the primary—and based on recent
data, superior—role of coronary stenting in
patients with ST-elevation MI comes from
investigators involved in the Stent versus
Thrombolysis for Occluded Coronary Arteries
in Patients with Acute Myocardial Infarction
Study (STOPAMI).
• The investigators concluded that in patients
with AMI, coronary stenting plus abciximab
produces a greater degree of myocardial
salvage and a better clinical outcome than
does fibrinolysis with a tissue plasminogen
activator
 GP IIb/IIa Inhibitors.
• In patients receiving PCI, among the GP
IIb/IIIa inhibitors, abciximab has
demonstrated consistent benefit.
• EPIC, EPILOG, EPISTENT trials, abciximab produced
4.5-6.4% absolute reductions in the 30-day composite
end point, and these benefits persisted at six months in
the EPIC and EPILOG trials
• The role of GP IIb/IIIa inhibitors in patients who
are not necessarily having a PCI is controversial.
All of the trials
PURSUIT
PRISM
PRISM-Plus
PARAGON
• included patients who did and did not receive PCI
and, importantly, the use of PCI was not
randomized.
• Differentiating the outcomes of patients who
received only medical therapy vs. those having
a PCI is not easy
 Oral Platelet Antagonists— The
Role of Clopidogrel Pretreatment

• The Clopidogrel in Unstable Angina to

Prevent Recurrent Events (CURE) trial
was designed to compare the efficacy and
safety of the early and long-term use of
clopidogrel plus aspirin with those of
aspirin alone in patients with ACSs and
no ST-segment elevation
• In the CURE, trial 12,562 patients
who had presented within 24 hours
after the onset of symptoms were
randomly assigned to receive
either clopidogrel (300 mg
immediately, followed by 75 mg
once daily) or placebo, in addition
to aspirin, for 3-12 months.
 THE FORGOTTEN THERAPIES.
• Aspirin
– ISIS 2 study.
• 23% reduction in mortality.
• Additive effect with thrombolysis
• Given as early as possible.

• Other trials have shown that it decreased death and MI

following UA by 31-50%.
 Some more antiplatelet agent
apart from aspirin
• GPIIb/IIIa inhibitors
Abciximab(Reopro)
Tirofiban (aggrastat).

• ADP inhibitors
Ticlopidine
Clopidogril(Plavix)

• Thromboxane synthetase inhibitors.

Ridogrel.
How do Glycoprotein IIB/IIIA
work?
• This mediates the last step/final common pathway for

platelet aggregation.

• GPIIb/IIIa are platelet-specific

• ~ 50 000 per platelet.

• The GPIIb/IIIa receptor is a functional receptor for such adhesive
macromolecules as

Fibrinogen

Fibronectin

Vitronectin

vWF

• Early use of GPIIb/IIIa inhibitors prevents disrupted coronary arterial

surfaces from supporting platelet deposition.
 THE FORGOTTEN THERAPIES.

• Beta Blockers.
– ISIS 1 (Lancet 1986)
• 16,027 patients
• 15% reduction in mortality
– Most trials pre thrombolysis
– TIMI 2b(TPA and iv BB)
• Decrease angina and reinfarction
• No change in mortality
 THE FORGOTTEN THERAPIES.

• GUSTO 1.
– Early iv use, limited value. Use oral when
stable.
• Beta Blockers.
– Long term therapy reduces mortality and reinfarction
by 25%.
– Early use of oral beta blockers in the first 24 hours is
recommended.
– Early iv use in selected patients.
 THE FORGOTTEN THERAPIES.

• ACE Inhibitors.
– ISIS 4 (Lancet 1995)
– 58,050 patients
– 7% reduction in mortality at 5/52
– 1/3 in first day and 1/2 in the first week
– Early therapy is indicated, within 24 hours
– Greatest benefit in LV dysfunction
 THE FORGOTTEN THERAPIES.

• Ca Channel Blockers.
– None of the trials has shown a reduction in
acute or long term mortality benefit in AMI.

• Nitrates
– ISIS 4.
– No significant reduction in 5/52 mortality.
– Routine long term use not supported.
 THE FORGOTTEN THERAPIES.

• Magnesium.
– Early studies including LIMIT ?benefit.
– ISIS 4 No benefit
– ? Time of administration
– ? Prior to reperfusion
– Further trials unlikely
ST elevation “ on arrival”::PTCA
• If it is available AND fast (1hr) then it is the
absolutely best Rx!Mortality moves from

1% @< 60 min
• to 6% @>90 min.
• I.e.approx lysis results.
• Average US data is 110 mins
ST elevation “ on arrival”::PTCA
• Some data from HERO shows if patient
present very early 1-3 hrs then lysis is equal
or better than PTCA.
• PTCA is better in delayed presenters.
ST elevation “ on arrival”::PTCA

• TAKE home message

• Have a cath ONLY if performed by a high volume
operator in a high volume facility AND in < 60 mins

• OTHERWISE CHOOSE LYSIS!

 NEW concept Facilitated PCI
PACT trial.
• Lyse stat with HALF dose rPA +Axicimab
• THEN go to lab and do angio only if clot
still present.
• The softer clot makes stenting easier.
• 93% high flow vs 82 %
 ST elevation “ on arrival”::::
CABG
• National incidence of CABAG during

admission of ACS is 9%
 ST elevation “ on arrival

• FUTURE PREDICTION
• 1 Everyone gets lysed!
• 2 THEN everyone gets
“cathed”
• 3 then stent or CABAG.
 Current practice.
• If you do not think they can be inside the
lab within the hour Perth figures 63 mins

• Then do not bother just get on and lyse.