State-of-the-Art-Cardiology-Practice: Management OF Acute Coronary Syndrome Professor M Zak Khalil, MD, FACC, FESC, FAHA

1. Acute Coronary Syndrome
(ACS)
Professor of Medicine
Consultant Interventional Cardiologist

2. Contents
• Definitions
• Assessment
• Treatment
• Discussion

3. Ischemic symptoms (Angina)
• Dull sub-sternal discomfort variably
described as a pressure or tightness
• Radiating to the left arm, neck, or jaw
• Associated with nausea, vomiting, sweating,
shortness of breath, or palpitations.
• Precipitated by stress
• Relieved by rest or nitroglycerin SL

4. Angina-equivalent
(No pain)
• Lightheadedness
• Shortness or breath
• Nausea
• Faintness
• Cold sweat

5. Coronary arteries.

6. Mechanical
obstruction
Thrombus
Dynamic
obstruction
Development of Coronary artery disease

8. Circulation. 2001;104:365-372
Atherosclerosis Unstable
angina
MI
ACSThrombosis

9. Unstable Angina (UA)
• Ischemic symptoms (history)
• No ST elevation or new Q waves (EKG)
• A normal serum CK-MB (enzymes)
WHO task force. Circulation 1979

10. Unstable Angina (UA)
• Ischemic symptoms suggestive of an ACS
• No elevation in troponins or CK-MB
• With or without ECG changes indicative of
ischemia (ST segment depression or transient
elevation or new T wave inversion)
The Joint ESC/ACC Committee.

13. Major Role of Platelets in ACS
Activated
platelets
•Adhesion1
•Activation2
•Aggregation3
Plaque
rupture
Fibrinogen
TxA2
ADP
Platelets
ADP = adenosine diphosphate
TxA2= thromboxane A2

14. Plaque rupture Fibrinogen-mediated platelet aggregation
Platelet-rich thrombus
formation and vessel occlusion
Acute
coronary
syndrome
Fibrinogen
GP IIb/IIIa receptor
Fibrin
Key to figures
Platelet adhesion & activation
Platelet Adhesion and Aggregation

15. CK- MB or Troponin Troponin elevated or not
ACS without persistent
ST-segment elevation
ACS with persistent
ST-segment elevation

16. ACS

18. MI (acute, evolving, or recent)
ESC/ACC/AHA 2012
Typical rise and gradual fall (troponin) or more rapid rise
and fall (CK-MB) of biochemical markers of myocardial
necrosis with at least one of the following:
• Symptoms of ischemia
• New (or presumably new) significant ST/T wave
changes or LBBB
• Development of pathological Q waves on ECG
• Imaging evidence of new loss of viable myocardium or
regional wall motion abnormality
• Identification of intracoronary thrombus by angiography
or autopsy

19. 0 1 2 3 4 5 6 7 8
Cardiac troponin-no reperfusion
Days After Onset of STEMI
MultiplesoftheURL
Upper reference limit
1
2
5
10
20
50
URL = 99th %tile of
Reference Control Group
100
Cardiac troponin-reperfusion
CKMB-no reperfusion
CKMB-reperfusion
Cardiac Biomarkers in STEMI
Alpert et al. J Am Coll Cardiol 2000;36:959.
Wu et al. Clin Chem 1999;45:1104.

20. NSTEMI
• NSTEMI = UA + myocardial damage
(as evidenced by release of detectable
quantities of a marker of myocardial injury).

21. Acute coronary
syndromes
Unstable angina (UA) Myocardial infarction
Stable angina NSTEMI STEMI

22. Ischemic Discomfort
at Rest
No ST-Segment
Elevation
NSTEMIUnstable
Angina
STEMI
ST-Segment
Elevation
( : positive cardiac biomarker)
Emergency
Department
In-Hospital
Presentation
Spectrum of Acute Coronary
Syndromes




23. European Survey of Acute Coronary Syndromes:
the ENACT Study
0
5
10
15
20
25
30
35
40
45
50
UA/non-ST elevation MI Definite MI Suspected ACS
Hospitalizations(%)
17 Western European countries Fox KA et al. Eur Heart J 2000; 21: 1440–9.

24. Repeat after GTN

25. Acute STEMI:
Chest pain duration to FMC = 30 min.

29. • All patients with ACS will receive the same
therapy.
• True:
• False:

30. • All patients with ACS will have the same
outcome.
• True:
• False:

31. • The mortality rate at one year is higher with
NSTEMI than STEMI.
• True:
• False:

32. Mortality STEMI NSTEMI UA
30 days 6.1% 5.7% 2.4%
6 months 8.0% 8.8% 5.0%
1 year 9.6% 11.1% 7.0%
GUSTO-IIb Investigators. Circulation 1998; 98:1860.
Prognosis of ACS

33. Mortality in Non-ST  ACS Patients With
Myocardial Infarction During Hospitalization
Fintel D, ACC, 2000
18.3%
5.5%
12.8% 
(P = 0.0001)
Patients with MI within
72 hours (n=593)
Patients without MI within
72 hours (n=8,868)
Days following randomization
%Mortality
30 60 90 120 150 180
20
15
10
5

34. Assessment
• TIMI risk score
• GRACE risk models
• Killip class

35. TIMI risk score
• Age > or =65 years
• Presence of at least three risk factors for CHD
• Prior coronary stenosis of > or =50 percent
• Presence of ST segment deviation on admission
ECG
• At least two anginal episodes in prior 24 hours
• Elevated serum cardiac biomarkers
• Use of aspirin in prior seven days

36. Mortality & Morbidity
(all-cause mortality, new or recurrent MI, or severe
recurrent ischemia requiring revascularization)
• Score of 0/1 – 4.7 %
• Score of 2 – 8.3 %
• Score of 3 – 13.2 %
• Score of 4 – 19.9 %
• Score of 5 – 26.2 %
• Score of 6/7 – 40.9 %

38. GRACE risk models
• Age
• Killip class
• Systolic blood pressure
• Presence of ST segment deviation
• Cardiac arrest during presentation
• Serum creatinine concentration
• Presence of elevated serum cardiac biomarkers
• Heart rate

39. Killip class
• Class I - no evidence of HF
• Class II - findings consistent with mild to
moderate HF (S3, lung rales less than one-
half way up the posterior lung fields, or
jugular venous distension)
• Class III - overt pulmonary edema
• Class IV - cardiogenic shock

40. Assessment
• It is essential that initial assessment and
management be:
• 1-Rapid
• 2-Methodical

41. Diagnostic evaluation in ER:
• Acute coronary syndrome
• Stable angina pectoris
• Nonischemic chest pain

42. All patients with ACS:
• Airway, breathing, and circulation
• 12-lead ECG
• Resuscitation equipment
• Cardiac monitor
• Oxygen
• IV access and blood work obtained
• Aspirin 300 mg
• Nitrates and morphine (unless contraindicated)

43. ST elevation (persistent):
• ST segment elevation > or =1 mm is
present in two or more anatomically
contiguous leads.
• The elevations are considered to represent
ischemia and not pericarditis or left
ventricular aneurysm.

47. ST elevation:

48. Coronary angiograms displayed a normal right coronary artery (A), which became totally
occluded during the ergonovine provocation test (B).
RCA
RCA

49. STEMI (ACS)
• Relief of ischemic pain
• Assessment of the hemodynamic state
• Clopidogrel
• Reperfusion with PCI or thrombolysis
• ACE-I (or ARB)
• Beta blocker
• Statin
• Anticoagulation for LV thrombus or chronic
atrial fibrillation to prevent embolization

50. Thrombolysis and ASA in Acute STEMI: ISIS-2
1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.
12.0%
9.2% 9.4%
11.8%
13.2%
8.0%
Placebo versus
streptokinase
Placebo versus
ASA 162 mg
Neither
versus both
5-weekmortality(%)
25%*
p <0.00001
23%*
p <0.00001
42%*
p <0.00001
*Odds reduction; ASA=acetylsalic acid
0
2
4
6
8
10
12
14

51. PCI versus Fibrinolysis
Favors
PCI
Favors fibrinolysis with
a fibrin-specific agent
13 RCTs
N = 5494
P = 0.04
AbsoluteRiskDifferenceinDeath(%)
30 40 50 60 70 80
PCI-Related Time Delay (minutes)
10 −
5 −
0 −
-5 − ┬ ┬ ┬ ┬ ┬ ┬
Nallamothu and Bates. Am J Cardiol 2003;92:824.

52. Reperfusion
• It is not possible to say definitively that a particular
reperfusion approach is superior for all pts, in all clinical
settings, at all times
• The appropriate & timely use of reperfusion therapy is
more important than the choice of therapy

54. Assessing Reperfusion Options for Patients
with STEMI
STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk
of thrombolysis, time for transport to PCI lab)
STEP 2: Determine whether fibrinolysis or invasive strategy is preferred*
Antman EM et al. Circulation 2004; 110: 588–636.
Fibrinolysis preferred if: Invasive strategy preferred if:
• Early presentation (<3 hours)
• Invasive strategy not an option
• Delay of invasive strategy
• Skilled PCI lab with surgical backup
available
• High risk (i.e. cardiogenic shock)
• Contraindications to fibrinolysis
• Late presentation (>3 hours)
• Diagnosis of STEMI is in doubt
*If presentation is <3 hours from onset and there is no delay to an invasive
strategy, there is no preference for either strategy

55. 2013 ACC/AHA Guidelines

73. Contraindications and Cautions
for Fibrinolysis in STEMI
Absolute
Contraindications
• Any prior intracranial hemorrhage
• Known structural cerebral vascular lesion (e.g.,
arteriovenous malformation)
• Known malignant intracranial neoplasm (primary
or metastatic)
• Ischemic stroke within 3 months EXCEPT acute
ischemic stroke within 3 hours
NOTE: Age restriction for fibrinolysis has been removed
compared with prior guidelines.

74. Contraindications and Cautions
for Fibrinolysis in STEMI
Absolute
Contraindications
• Suspected aortic dissection
• Active bleeding or bleeding diathesis
(excluding menses)
• Significant closed-head or facial trauma within
3 months

75. Contraindications and Cautions
for Fibrinolysis in STEMI
• History of chronic, severe, poorly controlled
hypertension
• Severe uncontrolled hypertension on
presentation (SBP > 180 mm Hg or DBP > 110
mm Hg)
• History of prior ischemic stroke greater than 3
months, dementia, or known intracranial
pathology not covered in contraindications
• Traumatic or prolonged (> 10 minutes) CPR or
major surgery (< 3 weeks)
Relative
Contraindications

76. Contraindications and Cautions
for Fibrinolysis in STEMI
Relative
Contraindications • Recent (< 2 to 4 weeks) internal bleeding
• Noncompressible vascular punctures
• For streptokinase/anistreplase: prior exposure (> 5
days ago) or prior allergic reaction to these agents
• Pregnancy
• Active peptic ulcer
• Current use of anticoagulants: the higher the INR,
the higher the risk of bleeding

77. Primary PCI for STEMI:
General Considerations
 Patient with STEMI (including posterior MI) or MI
with new or presumably new LBBB
 PCI of infarct artery within 12 hours of symptom
onset
 Balloon inflation within 90 minutes of presentation
 Skilled personnel available (individual performs > 75
procedures per year)
 Appropriate lab environment (lab performs > 200
PCIs/year of which at least 36 are primary PCI for
STEMI)
 Cardiac surgical backup available
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

78. PCI After Fibrinolysis
In patients whose anatomy is suitable, PCI should be
performed for the following:
Objective evidence of recurrent MI
Moderate or severe spontaneous/provocable
myocardial ischemia during recovery from STEMI
Cardiogenic shock or hemodynamic instability.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

79. Early vs. Late PCI

80. Hospital Care
Clopidogrel Therapy
Aspirin + clopidogrel, for up to 1 month*
Aspirin + clopidogrel, for up to 12 months
Withhold clopidogrel for 5-7 days for
CABG
* For patients managed with an early conservative strategy, and
those who are planned to undergo early PCI

81. CLopidogrel as Adjunctive
ReperfusIon TherapY1
Purpose:
To investigate whether clopidogrel would
produce greater angiographic and clinical
benefits over placebo for patients with acute
STEMI treated with fibrinolytics& ASA and
other standard care
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

82. Clopidogrel Improved Coronary Perfusion1
*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel
versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001)
Placebo
(n=1739)
Clopidogrel
(n=1752)
21.7
15.0
5
10
15
20
25
Primaryendpoint*(%)
36% reduction*
p <0.001
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

83. COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla
(Fibrinogen receptor)
Collagen thrombin
TXA2
Activation
TXA2
ASA
Synergistic Mode of Action with
Clopidogrel and ASA
. Schafer AI. Am J Med 1996; 101: 199–209.

84. Copidogrel in ACS (NSTEMI) CURE
20% RRR
p=0.00009
n=12,562
Benefits were seen within hours and
continued to increase over the 12 months
0 1 2 3 4 5 6 7 8 9 10 11 12
Months of follow-up
% of patients with recurrent ischemic event*
0
10
14
12
4
8
6
2
Standard therapy‡
Clopidogrel + standard therapy‡
The CURE Investigators. N Eng J Med August 2001
‡including ASA
*cardiovascular death, MI, or stroke

86. In patients for whom PCI is planned, clopidogrel
should be started and continued:
• ≥ 1 month after bare-metal stent
• ≥ 3 months after sirolimus-eluting stent
• ≥ 6 months after paclitaxel-eluting stent
• Up to 12 months in absence of high risk for
bleeding.

87. Safety1
Clopidogrel Placebo
(n=1733) (n=1719) p value
Primary bleeding endpoint (%)
TIMI major 23 (1.3) 19 (1.1) 0.64
Secondary bleeding endpoints (%)
TIMI minor 17 (1.0) 9 (0.5) 0.17
TIMI major or minor 40 (2.3) 28 (1.6) 0.18
Intracranial hemorrhage 8 (0.5) 12 (0.7) 0.38
Bleeding through 30 days (%)
TIMI major 33 (1.9) 30 (1.7) 0.80
TIMI minor 27 (1.6) 16 (0.9) 0.12
TIMI major or minor 59 (3.4) 46 (2.7) 0.24
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

91. NSTEMI (ACS)

92. 4.8
10.8
13.8
17.4
0.6
3.9
7.1
10.3
0
5
10
15
20
48 Hours 7 Days 30 Days 180 Days
Death/MI(%)
Placebo
Tirofiban
-90%
-68%
P = 0.04 P = 0. 02
Theroux, Am J Car 2001
-49%
P = 0.04
-54%
P = 0.03
Value of GPIIb/IIIa Antagonists (Tirofiban) Upstream in NSTEMI (ACS)
- Hospital with out catheterization facilities -

93. Theroux, Circulation 2000 – Roffi, Circulation 2001
9.3
15.5
19.2
1.2
4.7
11.2
0
5
10
15
20
25
7 Days 30 Days 180 Days
Death/MI(%)
-88%
-70%
P = 0.005 P = 0.001
-47%
P = 0.04
Placebo
Tirofiban
Value of Tirofiban upstream in high risk ACS
- Diabetics -

94. Enoxaparin
LMWH

95. Time to First Event (Triple Endpoint):
Superior efficacy of enoxaparin maintained to 43 days
UFH
Enoxaparin
Days from randomization
%ofpatientswithevents
Relative risk reduction 12%
P=0.048
19.7%
17.3%
4
8
12
16
20
0 8 16 24 32 40 43
Circulation 1999;100:1593-1601
Triple endpoint, death/myocardial
infarction/urgent revascularization
UFH, unfractionated heparin
The TIMI 11B Study

96. 25
20
15
10
5
0
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
UFH
Enoxaparin
Days from randomization
%ofpatientswithevents
P=0.019
P=0.017
Cohen M, et al. N Engl J Med 1997;337:447-52
MI, myocardial infarction
RA, recurrent angina
UFH, unfractionated heparin
Time to First Event over 30 Days: Death, MI, RA
Superior efficacy of enoxaparin was maintained to 30 days
The ESSENCE Study

97. Fondaparinux
in ACS

98. Action
• Synthetic heparin pentasaccharide
• Binds to AT with a higher affinity than the
native pentasaccharide of UFH or LMWH,
causing a conformational change in AT that
significantly increases the ability of AT to
inactivate factor Xa

99. OASIS 5: Efficacy and Safety of
Fondaparinux vs Enoxaparin in ACS
• Fondaparinux is compared to enoxaparin with substantially lower rates of
important bleeds.
• At 1- and at 6-month follow-up, the use of fondaparinux is associated with a
significant reduction in mortality.
• Strokes were also significantly reduced by fondaparinux.
• Similar results were observed in patients undergoing intervention.
• Therefore, according to the results of the OASIS-5 trial, fondaparinux is the
preferred anticoagulant for the treatment of acute coronary syndromes.

100. Fondaparinux
• Significant advantages compared to
enoxaparin in patients with a non-ST
elevation ACS
• Reductions in major bleeding during the
initial hospitalization
• Reductions in late mortality

101. Non ST-elevation ACS
ACS initial management
ECG monitoring, Blood samples
GpIIb/IIIa antagonist first
e.g., Tirofiban
Low risk
Positive Twice negative
Discharge
Stress test
Fondaparinux or Enoxaparin(or UFH),
ASA,
Clopidogrel*, Betablockers, Nitrates
Second troponin measurement
PCI, CABG or medical management
Depending upon clinical and angiographic features
Followd by Cor.
Angiography
High risk
TIMI score > 5
infusion of a GP IIb/IIIa receptor inhibitor followed by
(level of evidence A).

102. Conclusions:
• The key for correct treatment of ACS is
proper and swift assessment.
• STEMI needs rapid revascularization.
• Remember not to harm your patients while
acting fast!

103. 1) The preferred anticoagulant for the treatment of acute coronary syndrome (ACS) is:
A] Fondaparinux
B] Heparin
C] Enoxaparin
D] Tinzaparin
E] Warfarin
2) The mortality is higher at one year in patients with ACS diagnosed with:
A] STEMI
B] NSTEMI
C] Unstable angina
D] Chronic stable angina
3) The following is/are absolute contraindication for the use of thrombolytics:
A] Pregnancy
B] Active peptic ulcer
C] Recent (< 2 to 4 weeks) internal bleeding
D] Suspected aortic dissection
E] Any prior intracranial hemorrhage

104. 4) Clopidogrel is indicated in the following ACS:
A] STEMI
B] NSTEMI
C] Unstable angina
D] Patients who are candidates for CABG
E] None of the above
5) All patients with ACS should proceed for coronary angiogram.
A] True
B] False
6) All patients with ACS should be administered GPIIb/IIIa antagonist.
A] True
B] False
7) CABG remains the standard of care for patients with three-vessel or left main
coronary artery disease, since the use of CABG, as compared with PCI, resulted in
lower rates of the combined end point of major adverse cardiac or cerebrovascular
events at 1 year. (NEJM Feb.19, 2009).
A] True