Chest Pain Evaluation

Content.

• Brief overview.

• Risk factors

• Enzymes

• Cases

• Trial

Acute Coronary Syndromes

Unstable angina

ProgressiveRest

Post MI

Noncardiac

Variantangina

New onset anginaPrior CABG/PTCAPrior MI

NQWMI

What time of day is it?Non-ST Segment Elevation - Acute

Coronary SyndromesA Spectrum

Rest anginaRule-out MI

“Small”Infarctions

NQWMIU angina

CPK/troponinrise

“Large”Infarctions

QWMI NQWMI

A big pile ofA big pile ofspaghettispaghettiClinical TrialsClinical Trials

EPICEPIC

How do we makeHow do we makesense of this mess ?sense of this mess ?

EPILOGEPILOG PROLOGPROLOG

RAPPORTRAPPORT

ERASERERASER

CAPTURECAPTUREEPI-STENTEPI-STENT

IMPACTIMPACTIMPACT IIIMPACT II

IMPACT AMIIMPACT AMIPURSUITPURSUIT PARAGONPARAGON

PARADIGMPARADIGM

PRISMPRISM

PRISM-PLUSPRISM-PLUSRESTORERESTORE SPEEDSPEED

TIMI 14TIMI 14

TIMI 12TIMI 12

MINTMINT

AMIAMI

TIMI 9TIMI 9

HEROHERO

HIT IIIHIT III

GUSTO IIGUSTO II

ORBITORBIT SOARSOAR

TAMI 8TAMI 8

TIMI 11TIMI 11ESSENCEESSENCEFRISCFRISC FRICFRIC

REDUCEREDUCE

HELVETICAHELVETICA

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 AtherosclerosisThe Evolution of Atherosclerosis

FoamCells

FattyStreak

IntermediateLesion Atheroma

FibrousPlaque

ComplicatedLesion/Rupture

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

Growth Mainly by Lipid AccumulationGrowth Mainly by Lipid Accumulation Smooth Muscle& Collagen

Smooth Muscle& Collagen

Thrombosis,Hematoma

Thrombosis,Hematoma

Adapted From Stary HC et al. Circulation. 1995;92:1355-1374Adapted From Stary HC et al. Adapted From Stary HC et al. CirculationCirculation. 1995;92:1355-1374. 1995;92:1355-1374

Endothelial DysfunctionEndothelial Dysfunction

A paradigm issue

• Is it innocent till proven guilty• OR

• Guilty till proven innocent.

Acute chest pain ::::inputs

1 0 % S T ch a n g es 20% AM I 3 0 % U n sta b le a n g in a 4 0 % N o A C Sp ro b n o n ca rd ia c

C h est p a in

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 anginaUnstable anginaVariant anginaAMI

PericarditisValvular 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 CausesHerpes 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)@ triageRMO

• 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

Ischemia LVH

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 includeMyoglobinCK and its isoenzyme bandTroponin 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 toSubstantial 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.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

sweatingSOBDizziness

• 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:

• HistoryPresence of chest pain2 or > episodes of resting angina during the previous 24hrs.History of 3 or more cardiac risk factors

DiabetesSmokingElevated 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??

• Unlike UFH, enoxaparin has1.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.

Why Use Low Molecular Wt Heparin (LMWH)?.

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 bleeding3.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.

Thrombolytic • Immediately available

• No operator expertise

• Proven track record

• Many exclusions• More frequent bleeding complications

PTCA

• Few exclusions

• Very reasonable outcome

• Better initial flow

• Fewer bleeding complications

• Definition of anatomy

• 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 CPHaemodynamic instabilityNew ECGCHFDysrhythmias

• 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

Reteplaseor

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;

TIMITIMI 9B9B Risk Stratification

Prediction of Mortality at 30 Days

• Age > 70, • Prior MI• Anterior MI,• Atrial fibrillation• Rales• Hypotension and HR• Female gender• Diabetes

1.62.9

7.4

16

22.3

0

5

10

15

20

25

0 1 2 3 >4Number Risk Factors

Mo

rtal

ity

- 30

Day

s (%

)

P<0.001

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

Cannon CP et al. JACC 1999;33(Suppl. A):396A.

Hillis et al. TIMI 2

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.