Acute Coronary Syndromes

ACS: Definition
• A spectrum of clinical diagnoses
comprising unstable angina, Non-STEMI,
and STEMI that share similar pathological
features involving intracoronary thrombosis
ACS: Definition

From: Braunwald’s Heart Disease

 Pathophysiology
• atherosclerosis with superimposed coronary thrombosis
• Slowly growing high-grade stenoses can progress to complete
occlusion but do not usually precipitate acute STEMI d/t collateral
circulation
• During development of plaques, abrupt transition can occur, resulting
in
• Platelet activation
• Thrombin generation
• Thrombus formation
• Blood flow occlusion leads to imbalance between supply and demand
and could lead to myocardial necrosis
• Pts with non-transmural infarction more likely to have more significan
stenosis in IRA
• Less severe stenosis with lipid-laden plaques and fragile caps more
likely to rupture and causing thrombsis and STEMI
Stable Angina
Pathophysiology
•Progressive
narrowing of coronary
lumen
•Stable fibrous cap
STEMI
•Minimal prior
Unstable narrowing of
coronary lumen
Angina •Acute rupture of thin
•Progressive fibrous cap
narrowing •Occlusive thrombus
•Acute worsening of formation
coronary lumen due •Acute injury pattern
to thrombus •Myocardial necrosis
formation
NSTEMI
•Acute worsening of
coronary lumen due to
thrombus formation
•Sub-occlusive/
transient coronary
thrombus with
myocardial necrosis
ACS Evaluation
 Angina
• Definition: Discomfort in the chest/ “choking,” that
characteristically comes on with exertion, relieved by rest
and/or NTG
Favors Ischemic Against
Origin Ischemic Origin

Character Constricting
Squeezing
Dull ache
Knife-like, sharp
Burning Jabs
Heaviness Pleuritic

Location Substernal
Anterior thorax
Left submammary area
Left hemithorax
Arms, shoulders
Neck, teeth,
Interscapular

Provoking Exertion Pain after completion

of exercise
Excitement
Factors Cold, meals, stress Pain with movement
Likelihood that signs & symptoms represent an ACS secondary to CAD

Feature High Intermediate Low

History Chest or left arm pain or Chest or left arm pain or Probable ischemic
discomfort as chief discomfort as chief symptoms in absence of
symptom reproducing prior symptom the intermediate likelihood
documented angina Age > 70 characteristics
Known history of CAD, Male gender Recent cocaine use
including MI Diabetes mellitus

Exam Transient MR, hypotension, Extracardiac vascular Chest discomfort

diaphoresis, pulmonary disease reproduced by palpation or
edema or rales respiration

EKG New or presumably new, Fixed Q waves T wave flattening or

transient ST segment Abnormal ST segments or inversion in leads with
deviation (≥0.05mV) or T T waves not documented to dominant R wave
wave inversion (≥0.2mV) be new Normal EKG
with symptoms

Cardiac Elevated cardiac TnI, TnT Normal Normal

Marker or CK-MB

Braundwald 1994 AHCPR Publication No. 94-0602

 Chest Pain Classification
• Substernal
• Exertional
• Relieved with rest

• Interpretation
– Typical Angina: 3 criteria from above
– Atypical Angina: 2 criteria from above
– Non-Anginal Chest Pain: 1 or less criteria from
above
 Classification of Angina
• STABLE vs UNSTABLE
• CCS Classification for STABLE Angina
– I: No symptoms, or angina with strenuous exertion
– II: Slight limitation of ordinary physical activity
• Walking more than two blocks, climbing more than
one flight of stairs brings on angina
– III: Marked limitation of ordinary physical activity
• Walking less than two blocks, climbing less than
one flight of stairs
– IV: Any physical activity brings on angina; angina at
rest
 UA/NSTEMI
UA/NSTEMI 9/00
THREE PRINCIPAL PRESENTATIONS
Rest Angina* Angina occurring at rest and
prolonged, usually > 20 minutes

New-onset Angina New-onset angina of at least CCS

Class III severity

Increasing Angina Previously diagnosed angina that has

become distinctly more frequent,
longer in duration, or lower in
threshold (i.e., increased by > 1 CCS)
class to at least CCS Class III severity.
* Pts with NSTEMI usually present with angina at rest.
Braunwald
Braunwald
Circulation
Circulation 80:410;
80:410; 1989
1989
 Pre-Test Likelihood of CAD

Nonanginal pain Atypical angina Typical angina

Age (y.) Men Women Men Women Men Women

30-39 4 2 34 12 76 26

40-49 13 3 51 22 87 55

50-59 20 7 65 31 93 73

60-69 27 14 72 51 94 86

Diamond and Forrester, NEJM, 1979

Relationship of Rise in Biochemical
Markers to Onset of AMI
 Troponin

• cTnT (33 kDa) binds to

tropomyosin to complex
molecule to thin filament
• cTnI (24kDa) inhibits
actin-myosin interactions
• cTnC binds Ca2+

• Generally not detectable

in plasma of normal
persons
 Troponin
• TnT and TnI have different amino acid sequence in cardiac
vs. skeletal muscle
– Permits development of cardiac specific antibodies

• More sensitive and specific than CKMB

– Detects minimal amounts of cardiac necrosis (neg. CKMB)
• “minor myocardial damage/microinfarction”
– Elevated in MI (pos. CKMB)
– New guidelines suggest troponin is sufficient to dx MI

• Other situations assoc. with increased troponin:

• CHF
• ICU
• Renal failure
• CVA
• Myocarditis/other myocardial injury
 TROPONIN I LEVELS PREDICT THE
Changes
RISK OFin Focus onINHeart
MORTALITY Failure
UA/NSTEMI
patients)
of patients) 7.5
7.5
88

6.0
6.0
(% of

66
Days (%
42 Days

3.7
3.7
44 3.4
3.4
at 42
Mortality at

1.7
1.7
Mortality

22
1.0
1.0

831 174 148 134 50 67

00
00 to
to <0.4
<0.4 0.4
0.4 to
to <1.0
<1.0 1.0
1.0 to
to <2.0
<2.0 2.0
2.0 to
to <5.0
<5.0 5.0
5.0 to
to <9.0
<9.0 >9.0
>9.0
Cardiac
Cardiac Troponin
Troponin II (ng/ml)
(ng/ml)
Risk
Risk Ratio
Ratio 1.
1. 1.
1. 3.5
3.5 3.9
3.9 6.2
6.2 7.8
7.8

Antman
Antman N
N Engl
Engl JJ Med.
Med. 335:1342,
335:1342, 1996
1996
 TROPONINS T AND I
AS PREDICTORS OF MORTALITY
Total
Total Mortality
Mortality Cardiac
Cardiac Mortality
Mortality
6.9
6.9
77 6.4
6.4
66
5.0
5.0
55
44 3.3
3.3
33
2.0
2.0 1.7
1.7
22

11
00
PTS 1993
PTS 1993 1057
1057 RR
RR 1641
1641 792
792 RR
RR
Trop.
Trop. Neg
Neg Pos
Pos Neg
Neg Pos
Pos
No.
No. Trials
Trials 6 7
Prognostic Significance of Cardiac Troponin

N Engl J Med 1997;337:1648-53

Risk Stratification of Patients with ACS in ER
US/NSTEMI Rx
 Management of UA/NSTEMI
• 8 medication
• Oxygen
• ASA , clopidogrel
• Anticoagulant: UFH, LMWH
• Nitrates for pain
– Nitropatch 0.4 mg/hr x 12 hours daily
– IV NTG
• Beta-blocker
– Metoprolol 25-50 mg PO BID
• + Calcium channel blocker
• ACEI for secondary prevention
• Statin

• Investigations:
– Serial cardiac enzymes
– Definitive in-hospital risk stratification.
 Platelet Inhibitors in the ACS
• “A platelet GpIIb/IIIa receptor antagonist
should be administered, in addition to ASA
and UFH, to patients with continuing
ischemia or with other high risk features—”
• “Level of the evidence: A”

ACC/AHA Guideline Circulation 2000;102:1193-1209

 DEATH OR MI AT 30 DAYS

18 16.7
Placebo GP IIb-IIIa Inhibitor
14.1

14
11.6
Percent of Patients

10.9
10.1 10.2
9
10

5.9
6 4.8
3.9
3.6

1.8
2

0
EPIC CAPTURE EPILOG EPISTENT PRISM-PLUS PURSUIT

ACC Slide
 ANTIPLATELET Rx

Class I
Definite ACS with continuing
Possible ACS Likely/Definite ACS Ischemia or Other High-Risk
Features or planned PCI
Aspirin Aspirin Aspirin
+ +
Subcutaneous LMWH IV heparin
or +
IV heparin IV platelet GP IIb/IIIa antagonist

ACC Slide
 Other Antiplatelet Agents: Clopidogrel

Primary efficacy endpoints in the CURE trial

Endpoint Clopidogrel Placebo Relative p value
risk

CV 9.3% 11.4% 0.80 <0.001

death/MI/stroke

CV 16.4% 18.8% 0.86 <0.001

death/MI/stroke/
refractory
ischemia

The CURE Investigators. N Engl J Med 2001;345: 494-502.

Role at this point in combination with 2b3a inhibitor .

unclear: a useful option in ASA allergic pt’
Effect of Clopidogrel in ACS: the CURE trial

Bleeding results
Endpoint Clopidogrel Placebo p value

Major bleeding 3.7% 2.7% 0.001

Life-threatening 2.1% 1.8% 0.13

bleeding

The CURE Investigators. N Engl J Med 2001;345: 494-502.

 In Hospital Risk Stratification with
ACS: Principles
• Spectrum of risk
• Features associated with poor prognosis
(high probability of short term MI, etc.)
– EKG features: dynamic ST depression
– Cardiac markers: increased troponin
• Risk stratification refers to identifying
patients at risk
 Strategies for Risk Stratification
• Non-invasive
– EST
• Sensitivity 70%
• Specificity 70%

– MIBI scan
• Sensitivity 86-90%
• Specificity 90%

• Invasive
– Diagnostic coronary angiography
 Exercise Stress Testing
– Positive response: horizontal 1mm ST depression and
symptoms
– High risk response:
• Deep ST depression
• Poor exercise tolerance: unable to exercise past stage 2 (<6
mins)
• Exercise induced hypotension and dysrhythmias
– Uninterpretable:
• LBBB
• Digoxin
• LVH
– Contra-indications:
• Severe Aortic stenosis
• Aortic dissection
• MI/ACS within 24 h
• PE
 Angiography
• Gold standard
– Defines anatomy: 1VD, 2VD, 3VD, LM
– Assesses LV function
– Guides treatment: PCI, CABG or medical therapy

• Indications
– UA/post MI with ongoing pain, ST depresssion
– Hemodynamic instability
– CHF, ventricular arrhythmias
– Previous PCI, CABG
– High risk non-invasive test
– Emerging as the strategy of choice for initial evaluation of most
ACS with elevated troponins or EKG changes
• Based on FRISC II, TACTICS trials

• Strategy needs to be individualized.

Angiography
 Indications for Invasive Risk
Stratification Strategy in UA/NSTEMI
• Class I
– Recurrent ischemia at rest despite medical Rx
– Elevated troponin I or T
– New ST depression
– High risk findings on non-invasive testing
– Depressed LV function
– Hemodynamic instability
– Sustained VT
– PCI within 6 months
– Prior CABG

• In the absence of the above, either non-invasive or

invasive strategy can be followed.
ACC/AHA Guidelines for Management of UA/NSTEMI 2002
 SUMMARY: ER Evaluation of
Patient with Chest Pain
Symptoms
Suggestive of
Cardiac Origin?
NO YES
Consider
Alternative
Diagnosis

Stable Unstable

Early Risk Stratification in ER

SUMMARY: Management of UA/NSTEMI
HIGH RISK INTERM. RISK LOW RISK
(12-30%)* (4-8%) (<2%)
•Prolonged CP (>20 minutes •No high risk features but >=1 •No high or
or ongoing), plus:
•EKG: of: intermediated features
•Transient ST changes •Ongoing chest pain •Chest pain, single

*30 day rate of death or MI

•Sustained ST depr. •Crescendo angina episode, exertional
•Deep T wave inv. (>5 •Borderline positive •EKG: normal or
leads) troponin I (0.4-2.0) nonspecific or
•Biochemical markers: •Previous intervention: unchanged
•Troponin/CKMB PCI or CABG
abnormal •Increased baseline risk •May include previous
•Recurrent ischemia
•AMI in last 4 weeks (DM, elderly) hx of CAD or risk
•Hemodynamic compromise factors

•ASA + heparin/LMWH •ASA + clopidogrel •ASA

•GP IIb/IIIa •UFH or LMWH •No heparin
•Early cardiac cath •Cardiac cath lab •Observe/outpt tests
 STEMI
• WHO defn: 2 of
– characteristic chest pain
– ECG changes – ST elevation
– Biochemical changes
• ACC + ESC
– Rise and fall of biochemical marker (Tn, CK-MB) +
one of
• ischemic symptoms
• development of pathological Q waves
• ECG changes suggestive of ischemia
• Coronary angiography
 STEMI
• More than 1 million MI’s per year in US
• Fatal in 1/3 of pts, ½ of death occurs within
1 hr of symptoms (arrhythmias)
 Symptoms
• prolonged pain > 30 min usually
• constricting, crushing, or compressing; heaviness or
squeezing
• can be choking, burning, knife-like
• retrosternal, radiating to L>R side of chest, ulnar sides of
arms L>R, shoulder, upper extremity, jaw, neck,
interscapular region sometimes epigastric
• pain usually implies ischemia
• other sx
– nausea/vomiting more common in inferior MI
– weakness
– dizziness
– palpitation
– cold perspiration
– sense of impending doom
 STEMI
• Pre-hospital care
– EMS
• Dispatch, first response, EMS ambulance
• AED to first responders
• Relief of pain to reduce sympathetic tone
• Rapid transfer to hospital
– Prehosp fibrinolysis
• Some evidence suggesting improved mortality
 STEMI
• ER Management
– Early recognition
• Ischemic type chest pain
• ECG signs
– ECG monitor rhythm
– IV access
– O2
– Reperfusion strategy will depend on
• Time since symptoms
• Risk assoc with STEMI
• Risk of lytics
• Time required for PCI
Time to Rx
 STEMI - Acute Rx
• ASA
– Block formation of thromboxane A2 in platelets by blocking cox
– Chew 160-325 mg to allow for buccal absorption
• Pain control
– Try to decrease sympathetic activity
– Analgesics
– Nitrates
• Coronary vasodilation, decrease preload by increasing venous
capacitance
• Avoid if suspect RV infarct
– Beta blockers
• Reduce HR, decrease myocardial oxygen demand
• Reduce pain
• Reduce the need for analgesics
• Reduce infarct size
– Oxygen
 STEMI - Reperfusion

• “Time is muscle”
• Increased mortality with delay in reperfusion
regardless of strategy
• Less time:
– Recovery of LV systolic fxn
– Improved diastolic dysfxn
– Reduced mortality
– Post ischemic contractile dysfxn can occur after
reperfusion
– Myocardial stunning
 STEMI - Lytics
• Benefits
– Recanalize thrombotic occlusion
– Restores coronary flow
– Reduce infarct size
– Improves myocardial function
– Improves survival
– May result in microvascualr damage and
reperfusion injury
– STR strong predictor of reperfusion
 STEMI - lytics
• GISSI first trial to demonstrate benefit of
streptokinase
• Other fibrinolytics
– Alteplase (t-PA)
• GUSTO I
– Reteplace (rtPA)
• GUSTO III (equivalence)
– Tenecteplase (TNK)
• ASSENT II (equiv with t-PA)
Evidence for Fibrinolysis: GISSI

n >11,000

ARR: 2%
RRR: 18%

Circ. 1998
Comparison of Thrombolytics:
GUSTO

n=>41,000

ARR 0.9%
RRR 12.5%

NEJM, 1993
ASSENT 2
• N= 16949
• Design: non-inferiority

• Trend toward decrease in

bleeding
• Improve ease of use with
Bolus infusion
• Combination with heparin
IV

Lancet 1999; 354: 716-22

Time to Rx
Efficacy of Thrombolysis: Subgroups

n=56,800

Fibrinolytic
Therapy
Trialists’ Group.
Lancet, 1988
 Choosing a Fibrinolytic
• Patients in whom t-PA is proven superior to SK:
– Age < 75
– Anterior MI, presenting within 4 hours
– High risk/extensive MI at other site within 4 hours
– Cardiogenic shock
– Previous SK exposure
• TNK = rtPA > tPA
– Easy administration
– Lower chance of med error
– Less non-cerebral bleeds
• Patients in whom SK appears to be equivalent to t-PA:
– Inferior, posterior or lateral MI
– MI at any site after 6 hours
– Age > 75 years
Bleeding complications with Lytics

• Major bleeding 0.5-2%

• Minor bleeding: 10-20 %
• Intracranial hemorrhage: 0.5-2%

• Management:
– D/C thrombolytic
– Cryoprecipitate (fibrinogen enriched)
– If heparin, give protamine sulfate
 Indications for Primary PCI
• Class I
– Alternative to thrombolytic if performed in a timely fashion by
skilled individuals
– Patients within 36 hours of AMI, with cardiogenic shock, <75
years
• Class IIa
– Contraindication to thrombolysis
• Class IIb
– NSTEMI within 12 hours, with less than TIMI II flow in infarct
related artery
• Class III
– Elective PCI of non-IRA at time of AMI
– Beyond 12 hours of symptoms, no evidence of ischemia
– Successful thrombolysis
From ACC/AHA Guidelines, 2000
 STEMI -PCI
• Meta analyis shows improved clinical
endpoints favoring PCI
– Factors to consider
• Time to treatment
• Risk of STEMI
• Cardiogenic shock
• Kilip class >= II
• Risk of bleeding
• Time to transport to skilled PCI center
 STEMI – Other Rx
• ASA
– ISIS-2
• Thienpyridines
– Clopidogrel
• CLARITY
– Ticlopidine
• Inhibit binding to adenosine diphosphate receptor
• GPIIb/IIIa inhibitors
– Abciximab
– Tirofiban
– Eptifibatide
• GUSTO V
– rtPA vs 1/2rtPA and abciximab
– similar efficace endpoints but increased bleeds with IIb/IIIa
ASA: ISIS 2

n > 17, 000

Lancet, 1988
 STEMI – Other Rx
• Heparin
– reduces reinfarction, stroke, PE
– reduces mortality in pts receiving lytic
• LMWH
– ASSENT III showed benefit over UFH in pts
receiving TNK
• Others
– Bivalirudin (HITT)
 Post- STEMI Rx
• BB
• ACEi
– Prevents ventricular remodeling
– Improved hemodynamics
– Reduces CHF
– Selected population: (long-term, started day 3-16)
• SAVE
• AIRE
• TRACE
– Unselected pop (short term, started early)
• GISSI 3
• SMILE
• ISIS-4
• CCS-1
 Post- STEMI Rx
• ARB
– OPTIMAAL (losartan)
– VALIANT (valsartan)
• Aldasterone antagonists
– EPHESUS (acute MI, LV dysfxn, HF)
– Reduction in mortality
• Statins
– PROVE-IT
 Mechanical Complications of MI
Variable
VSD Free Wall Papillary
Rupture Muscle Rupture
Age 63 69 65
Days, post MI 3-5 3-6 3-5
Anterior MI 66% 50% 25%
New Murmur 90% 25% 50%
Thrill Yes No Rare
Previous MI 25% 25% 30%
Echo: VSD Pericardial Flail leaflet
Effusion MR
PA catheter: O2 step-up Equalization of Prominent V-
RA-RV diastolic press. wave
Mortality:
Medical 90% 90% 90%
Surgical 50% ? 40-90%
 Other Complications
• Arrhythmias
– Electrical instability
• VPB
• VT
• VF
• AIVR
– Pump failure/inc symp drive
• Sinus tachy
• AFib/Flutter
• SVT
– Brady/conduction
• Sinus brady
• Junctional escape
• AVB
 Other Complications
• Recurrent chest pain
– Distinguish reinfarction from recurrent
ischemia from non-ischemic chest pain
• Pericarditis
• LV aneurysm
 Risk Stratification
• survival after STEMI depends on
– LV fxn
• Stress/pharma Echo, PET
– Residual potentially ischemic myocardium
• Submaximal ETT
– Susceptibility to vent arrhythmias
Risk Stratification
 Discharge Planning
• usually 5 days post STEMI
• counseling
– ambulation but avoid heavy lifting
– graded activity (symptom limited)
– Rehabilitation
Questions