1. Grerk Sutamtewagul, M.D.
June 2012

2. Outline
 Definition
 Pathophysiology
 Clinical Presentation
 Risk Stratification
 Early Hospital Care
 Medical treatment
 Treatment strategy
 Long Term Management

3. Unstable angina and
Non-ST Elevation Myocardial Infarction

4. Unstable angina
 Angina pectoris or equivalent type of
ischemic discomfort with at least 1/3 of
the following
1. Occurring at rest and lasting > 20 mins
2. New onset, severe symptom
3. Crescendo pattern (increasing in
severity, duration, or frequency)

5. NSTEMI
 Approximately 2/3 of patient with UA
have elevated cardiac serum markers –
thus the diagnosis of NSTEMI

6. Unstable angina
and Non-ST Elevation Myocardial Infarction

7. Pathophysiologic process
1. Plaque rupture or erosion with
superimposed thrombus*
2. Dynamic obstruction
 Spasm of epicardial artery (Prinzmetal)
 Constriction of small intramural arteries
 Local vasoconstrictors (e.g. TXA2) released
from platelets
 Dysfunction of coronary endothelium
 Adrenergic stimuli (cold, cocaine)

8. Pathophysiologic process
3. Severe coronary luminal narrowing
 Atherosclerosis
 Post-PCI restenosis
4. Inflammation
5. Secondary unstable angina to
tachycardia, fever, hypotension, anemia

9. Plaque rupture and thrombosis
 Platelet activation and aggregation
 Exposure to subendothelial matrix (tissue factor,
collagen)
 Platelet adhesion (GP Ib-vWF and GP VI-
collagen)
 Platelet activation:
○ Morphology change (smooth  spiculated)
○ Degranulation (TXA2, serotonin, etc.)
○ GP IIb/IIIa receptor expression and enhancement
 Platelet aggregation (GP IIb/IIIa – fibrinogen)
 Secondary hemostasis

11. Plaque rupture and thrombosis
 Platelet activation and aggregation
 Secondary hemostasis
 Initiation
 Amplification
 Propagation

14. Unstable angina
and Non-ST Elevation Myocardial Infarction

15. Clinical Examination
 Largely unremarkable
 Signs of large fraction ischemia:
 Diaphoresis
 Pale, cool skin
 Sinus tachycardia
 Third or forth heart sound
 Basilar rales
 Hypotension

16. Electrocardiography
 EKG abnormality found in 50% of
patients with UA/NSTEMI
 ST depression (>0.1 mV or >0.05 mV if
prior EKG available)
 Transient ST elevation (10%, poor
prognosis)
 T wave change (sensitive but not
specific unless > 0.3 mV)

17. ST segment

18. 51 yo F with CP+SOB

19. 5 hrs later

20. Markers of Cardiac
Necrosis
 CK-MB
 Troponin T, Troponin I
 Higher level associates with worse
prognosis.
 Patients with UA/NSTEMI and troponin
elevation but no apparent CAD on
angiography had significantly worse
prognosis than those who have troponin
negative1.
1. Braunwald E, Lakkis N; TACTICS-TIMI-18 Investigators. Prognostic implications of
elevated troponin in patients with suspected acute coronary syndrome but no critical
epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol. 2005
Jan 4;45(1):19-24. Erratum in: J Am Coll Cardiol. 2005 Jun 7;45(11):1911.

22. Laboratory testing
 Serum lipid panel – treatable risk factor
 Total Cholesterol and HDL-C fall by as
much as 30-40% in 24 hrs after
UA/NSTEMI or STEMI.

23. Unstable angina
and Non-ST Elevation Myocardial Infarction

24. High-risk clinical subgroups
 Age
 PURSUIT trial: univariate relationship
between age and 30-day mortality was
curvilinear with reflection at around 65 years
in UA/NSTEMI.
Boersma E et al. Predictors of outcome in
patients with acute coronary syndromes without
persistent ST-segment elevation. Results from
an international trial of 9461 patients.
The PURSUIT Investigators.
Circulation. 2000 Jun 6;101(22):2557-67.

25. High-risk clinical subgroups
 Gender
 Women with ACS tend to have more
traditional risk factors  confounded
 Women usually presents with more atypical
features  delay in diagnosis
 Women with presumed ACS have less
severe epicardial CAD.
 Multivariate model: gender was not
associated with cardiovascular outcomes2.
2 Hochman JS, et al. Outcome and profile of women and men presenting with acute coronary syndromes:
a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1997
Jul;30(1):141-8.

26. High-risk clinical subgroups
 Diabetes
 Potent risk indicator
 Increase in oxidative stress 
proatherogenic
 Risk of first MI in diabetics without prior MI is
approximately equal to recurrent MI in non-
diabetics who had prior MI*.
* Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality
from coronary heart disease in subjects with type 2 diabetes and in nondiabetic
subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul
23;339(4):229-34.

27. Mortality comparison
Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2
diabetes and in nondiabetic subjects with and without prior myocardial infarction. N
Engl J Med. 1998 Jul 23;339(4):229-34.

28. High-risk clinical subgroups
 Diabetes
 1.5 to 2.0-fold higher rate of death and
cardiac ischemic events for patients with
NSTEMI (GUSTO IIb, PRISM-PLUS, FRISC II,
TACTIC-TIMI 18, GUSTO IV-ACS)
 Data across 11 TIMI trials:
○ 30-day mortality adj OR 1.78 [1.24-2.56]
○ 1-yr mortality adj HR 1.65 [1.30-2.10]

29. High-risk clinical subgroups
 Smoking
 Smoker‟s Paradox
○ Current smokers tend to have lower rates of
death and ischemic events than nonsmokers.
 Multivariate analysis: smoking is not a
significant independent prognostic factor.*
* Barbash GI, et al. Evaluation of paradoxic beneficial effects of smoking in patients receiving
thrombolytic therapy for acute myocardial infarction: mechanism of the "smoker's paradox" from
the GUSTO-I trial, with angiographic insights. Global Utilization of Streptokinase and Tissue-
Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol. 1995 Nov 1;26(5):1222-
9.

30. High-risk clinical subgroups
 Peripheral vascular disease
 Independent risk factor for death and
ischemic complications in patients with UA-
NSTEMI even after adjustment for traditional
risk factors. (OPUS-TIMI 16, PURSUIT study)

31. High-risk clinical subgroups
 Prior aspirin use
 Multiple studies have confirmed that patients
with prior aspirin use are at increased risk.
 Present of aspirin-resistant platelet-rish
thrombi.
 Aspirin resistance may be associated with
increased risk of death and cardiovascular
complications.

32. High-risk clinical subgroups
 Severity of angina
 Worse prognosis with
○ Multiple episodes of angina in the past 24 hrs
○ Angina at rest
○ Post-infarction angina

33. High-risk clinical subgroups
 Physical examination
 Physical exam suggestive of LV dysfunction
is more commonly seen in STEMI.
 Higher Killip class (≥2)  significant
underlying CAD  higher mortality

34. Holmes DR Jr et al. Cardiogenic shock in patients with acute ischemic
syndromes with and without ST-segment elevation. Circulation. 1999
Nov 16;100(20):2067-73.

35. High-risk clinical subgroups
 Electrocardiogram
 Admission ECG is one of the most useful and
powerful predictors of adverse outcomes.
 ST depression is associated with
○ Worse in-hospital prognosis
○ Greater complexity and extent of the lesion
 ST depression as little as 0.05 mV had ≈ 2 fold
death or MI at 30 days and 1 year [TIMI III Registry]
 T wave inversion is generally not assoc with
worse prognosis (except deep TWI lateral leads)

36. High-risk clinical subgroups
 Markers of necrosis
 Blood samples should be obtained at least 6
to 9 hours after the onset of symptoms
 There is a quantitative relationship between
the magnitude of CK-MB, Troponin I and risk
of death [PURSUIT, TIMI IIIb].

37. Troponin I and mortality
Antman EM, et al. Cardiac-specific troponin I levels to predict the risk of mortality in
patients with acute coronary syndromes. N Engl J Med. 1996 Oct 31;335(18):1342-9.

38. What should be the appropriate
cut point of troponin assay?
 Consensus panels recommend cut point at
99th percentile from a cohort of healthy
individuals and coefficient of variation less
than 10% (for study precision).
 Trials of UA-NSTEMI supported the
prognostic importance of “low-level”
troponin elevation even below such cut
point [data from TACTIC-TIMI 18]

39. Death, MI, ACS vs Troponin
Morrow DA, et al; TACTICS-TIMI 18 Investigators.
Ability of minor elevations of troponins I and T to predict benefit from an
early invasive strategy in patients with unstable angina and non-
ST elevation myocardial infarction: results from a randomized trial. JAMA.
2001 Nov 21;286(19):2405-12.

40. Emerging Biomarkers in
ACS

42. Integrated Approach
 TIMI risk score
 GRACE risk score
 Prognostic tools with high discriminatory
ability using baseline variables which
are parts of routine medical evaluation.

43. TIMI Risk Score for
UA/NSTEMI
 Data from 1957 patients who were
randomized to the UFH arm of TIMI 11B
trial (UA/NSTEMI only) 
Multivariated logistic regression analysis 
7 independent predictors.
 TRS for UA/NSTEMI has been validated in
many cohorts, including ESSENCE and
TACTICS-TIMI 18.

44. TIMI Risk Score for
UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST
elevation MI: A method for prognostication and therapeutic
decision making. JAMA. 2000 Aug 16;284(7):835-42.

45. TIMI Risk Score for
UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST
elevation MI: A method for prognostication and therapeutic
decision making. JAMA. 2000 Aug 16;284(7):835-42.

46. TIMI Risk Score for
UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST
elevation MI: A method for prognostication and therapeutic
decision making. JAMA. 2000 Aug 16;284(7):835-42.

47. GRACE risk score
 Data from Global Registry of Acute
Coronary Events (GRACE) with 15,007
subjects across the spectrum of ACS 
9 predictive variables.

49. Comparison of TRS for
UA/NSTEMI and GRACE score
 Retrospective analysis and prospective
observational studies suggest that
GRACE score has greater prognostic
discrimination compared to TRS for
UA/NSTEMI.
 One retrospective analysis found no
difference between GRACE score and
TRS for STEMI.

50. TRS vs GRACE score
Ramsay G, Podogrodzka M, McClure C, Fox KA. Risk prediction
in patients presenting with suspected cardiac pain:
the GRACE and TIMI risk scores versus clinical evaluation. QJM.
2007 Jan;100(1):11-8. Epub 2006 Dec 15.

51. Unstable angina
and Non-ST Elevation Myocardial Infarction

52. Early hospital care
 General and anti-ischemic therapy
 Antiplatelet therapy
 Anticoagulant therapy
 ACEI or ARB
 Treatment strategies: initial conservative
vs early invasive

53. General Measures
 Patient at medium-high risk should be
admitted to intensive or intermediate cardiac
care unit + ECG monitoring
 Bed rest
 Oxygen for SaO2 less than 90%, respiratory
distress, other high-risk features for
hypoxemia (Class I),
 or all patient with UA/NSTEMI in the first 6 hours
(Class IIa)
 Anti-ischemic therapy: Nitrate, beta-blocker
 Intravenous Morphine
 for uncontrolled CP despite NTG. (Class IIa)

54. Anti-ischemic therapy
 NITRATES
 Endothelium-independent vasodilators (via
G protein and cAMP)
 Coronary vasodilation
 Arteriolar and venous dilation  reduced
myocardial afterload, preload, and wall
stress

55. Anti-ischemic therapy
 NITRATES
 0.4 mg NTG Sublingual q5mins x 3
 0.3-0.6 mg NTG Buccal spray q5mins x 3
 If symptoms persist, IV NTG start at 5-10
μg/min, increase by 10 μg/min q3-5mins
until relief of symptoms.

56. Anti-ischemic therapy
 NITRATES
 IV NTG should not be increased if it will
preclude the use of beta-blocker or ACEI.
 Contraindications: Hypotension, use of
sidenafil or related phosphodiesterase-5
inhibitors within previous 12-48 hours,
HR<50, or HR >100 in the absence of
symptomatic HF or RV infarction
 8-10 hours of nitrate-free interval to avoid
the development of tolerance
 No effect on mortality [ISIS-4]

57. Beta-blockers
 Reduce subsequent MI or recurrent
ischemia† and rate of VF‡, reduction in
mortality in early placebo-controlled trials
 Reduction in mortality in 21st century is less
clear.
 Chen et al∏. 45,852 subjects - Metoprolol vs
Placebo in MI: Death OR 0.99, [0.92-1.05]
[COMMIT trial]
† Gottlieb SO, et al. Effect of the addition of propranolol to therapy with nifedipine for
unstable angina pectoris: a randomized, double-blind, placebo-controlled trial.
Circulation. 1986 Feb;73(2):331-7.
‡ Yusuf S, et al. Beta blockade during and after myocardial infarction: an overview of
the randomized trials. Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):335-71.
∏ Chen ZM, et al; COMMIT collaborative group. Early intravenous then
oral metoprolol in 45,852 patients with acute myocardial infarction: randomised
placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32.

58. Beta-blockers
 Oral beta-blocker should be initiated within
the first 24 hours (Class I) for pt without
contraindication and ≥ 1 of the following:
 Signs of HF
 Low output state
 At risk for cardiogenic shock
○ Age>70, SBP<120mmHg, HR<60 or >110
 Relative contraindications: PR >240ms, 2nd or
3rd degree heart block, active asthma, Reactive
airway

59. Calcium channel blocker
 Calcium channel blockers
 vasodilatory effects, reduce blood pressure,
slow heart rate and reduce myocardial
contractility
 Reduce recurrent MI in early studies
 Non-dihydropyridine (Verapamil, Diltiazem)
should be used.
 Short-acting dihydropyridine CCB (e.g.
Nifedipine), which accelerate HR, has been
shown to be harmful when it is not
coadministered with beta-blocker.
 Long-acting dihydropyridine CCB is safe for
stable CAD.

60. Calcium channel blocker
 In whom beta blockers are
contraindicated, a nondihydropyridine
CCB should be given as initial therapy.
(Class I)
 in the absence of significant LV dysfunction
 For recurrent ischemia after beta blocker
and nitrates have been fully used, oral
long-acting nondihydropyridine CCB can
be used (Class IIa)

61. Antiplatelet Therapy
 Platelets play a major role in
pathogenesis of UA/NSTEMI.
 Accordingly, antiplatelet therapy plays a
central role in management.
 Antiplatelets:
 Aspirin
 ADP receptor (P2Y12) antagonist
 Glycoprotein IIb/IIIa (αIIbβ3) inhibitor

62. Antiplatelets

63. Aspirin
 Irreversibly acetylates platelet
cyclooxygenase 1 (COX-1)  decrease
synthesis and release of Thromboxane
A2 (TXA2), a major platelet activator.
 Antiplatelet effect lasts for lifetime of the
platelets (7-10 days).

64. Aspirin
 Several trials have demonstrated clear
beneficial effects of ASA in UA/NSTEMI.
 Approximately 25% reduction in death or
MI
 Efficacy is not dose-dependent.
 CURRENT-OASIS 7 compared high-dose
(300-325 mg) versus low-dose (75-100 mg)
aspirin daily after a loading dose  No
difference in death, MI, stroke, major
bleeding in 30 days.†
† Mehta SR, et al. CURRENT-OASIS 7 Investigators. Dose comparisons of
clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010
Sep 2;363(10):930-42. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.

65. Aspirin

66. Aspirin
 Aspirin resistance
 2-8% of patients have limited anti-platelet
effect
 Lead to worse cardiovascular outcome
 Often related to poor compliance
 Concomitant use of ibuprofen (reversible
COX-1 inhibitor – competitively bound to
COX-1)

67. Aspirin
 ASA should be administered to patients
with UA/NSTEMI as soon as possible
after hospital presentation and
continued indefinitely in patients who
tolerate it. (Class I, LOE A)
 Clopidogrel can be used if the patients
who are unable to take aspirin. (Class I,
LOE B)

68. ADP antagonist
 Thienopyridines
 Ticlopidine
 Clopidogrel
 Prasugrel
 Elinogrel
 Non-thienopyridines
 Tigagrelor
 Cangrelor

69. ADP antagonist
Cattaneo M. New P2Y(12) inhibitors. Circulation.
2010 Jan 5;121(1):171-9.

70. Thienopyridines
 Prodrugs
 Oxidation by P-450 system in the liver
 Active metabolites irreversibly inhibit the
binding of ADP to platelet P2Y12
receptor  inhibit platelet aggregation.
 Ticlopidine is the first thienopyridines. Its
use was limited by bleeding
complication, neutropenia, and risk of
TTP.

71. ADP antagonist

72. Clopidogrel
 Absorption  85% Hydrolyzed  P-450
oxidation (mainly cytochrome 2C19)
 As effective as ticlopidine for prevention of
stent thrombosis but less bleeding
complication.
 CURE trial: 12,562 UA/NSTEMI patients
ASA + heparin + clopidogrel or placebo 
20% reduction in cardiovascular death, MI
or stroke in all groups (high-low risk, PCI-
medical-CABG). Benefit seen from first 24
hours and extended through the 1-year
period of the study.

73. Figure 1. Cardiovascular death, MI, or stroke for entire study.
Fox K A et al. Circulation 2004;110:1202-1208
Copyright © American Heart Association

74. Clopidogrel before PCI
 Clopidogrel given before PCI
 29% reduction in cardiovascular death or MI
 Benefit even without concomitant GP IIb/IIIa
inhibitor
Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy
(CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28
Investigators. Effect of clopidogrel pretreatment before
percutaneous coronary intervention in patients with ST-elevation
myocardial infarction treated with fibrinolytics: the PCI-CLARITY
study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.

75. CLARITY-TIMI 28
Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy
(CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28
Investigators. Effect of clopidogrel pretreatment before
percutaneous coronary intervention in patients with ST-elevation
myocardial infarction treated with fibrinolytics: the PCI-CLARITY
study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.

76. Clopidogrel before CABG
 In patient undergoing CABG, clopidogrel
given within 5 days before surgery is
associated with major bleeding
complication and longer hospital stay
(not statistically significant).

77. Figure 3. Major bleeding (point estimates and CIs) for study as a whole.
Fox K A et al. Circulation 2004;110:1202-1208
Copyright © American Heart Association

78. TABLE 4
The time interval between study drug discontinuation and early
CABG surgery in relation to bleeding frequency
Life threatenting or other major bleeds within
7 days of CABG surgery
Placebo Clopidogrel RR 95% CI
% %
Day of CABG 6/119 5 9/110 8.2 1.62 0.60-4.41
1 day prior to CABG 11/139 7.9 11/99 11.1 1.4 0.63-3.11
2 days prior to CABG 7/95 7.4 12/118 10.2 1.38 0.57-3.37
3 days prior to CABG 3/73 4.1 5/54 9.3 2.25 0.56-9.02
4 days prior to CABG 3/50 6.0 5/55 9.1 1.52 0.38-6.02
≥5 days prior to CABG 24/454 5.3 20/456 4.4 0.83 0.46-1.48
Fox K A et al. Circulation 2004;110:1202-1208

79. Strategies for initiation of
clopidogrel therapy
 Start at presentation
 Start immediately after PCI

80. Strategies for initiation of
clopidogrel therapy
 Start at presentation
 Reducing ischemic event before PCI
 Increase bleeding in pt who undergo CABG
 Start immediately after PCI
 Decrease bleeding, blood transfusion,
immediate post-op death

81. Strategies for initiation of
clopidogrel therapy
 Overall benefit-to-risk ratio from major
randomized studies favors early
initiation of clopidogrel.
Biancari, et al. J Thorac Cardiovasc Surg, Mar 2012

82. Loading dose
 Initial loading dose decrease the time
achieving target level.
 Clopidogrel 75 mg/day  3-5 days
 Clopidogrel 300 mg loading  4-6 hrs
 Clopidogrel 600 mg loading  2 hrs

83. Loading dose
 Clopidogrel 600 mg vs 300 mg loading
 Lower rate of major cardiovascular event
[ARMYDA-2]
 No difference in cardiovascular death, MI, or
stroke [CURRENT-OASIS 7]
 Review of literature:
 Decrease major adverse cardiovascular
events
 Marginally decrease all-cause mortality
 Slightly increase bleeding risk

84. Nijjer SS, et al. Quantitative comparison of clopidogrel 600mg, prasugrel and
ticagrelor, against clopidogrel300mg on major adverse cardiovascular events
and bleeding in coronary stenting: Synthesis of CURRENT-OASIS-7, TRITON-
TIMI-38 and PLATO. Int J Cardiol. 2012 Jul 12;158(2):181-5. Epub 2012 Jan 10.

85. Clopidogrel
hyporesponsiveness
 Common among
 Diabetics
 Obesity
 Advanced age
 Genetic polymorphism in cytochrome P450
(esp. CYP2C19 - *C2 allele)
○ 1/3 of Whites, more frequent in Asians
○ Related with adverse outcome and in stent
thrombosis

86. Clopidogrel and PPI
 Proton-pump inhibitors (PPI) are often
prescribed prophylactically to prevent GI
bleeding due to dual-antiplatelet therapy.
 Some PPIs inhibit CYP2C19:
omeprazole, lansoprazole, rabeprazole
but not pantoprazole
 Some observational studies reported
adverse cardiovascular outcome with
PPI-clopidogrel-ASA.

87. Clopidogrel and PPI
 2 randomized trials: PRINCIPLE TIMI-44 and
TRITON TIMI-38
 PPI treatment attenuated the
pharmacodynamic effect of clopidogrel.
 PPI treatment did not affect the clinical
outcome. The finding was true for all PPIs
including omeprazole and pantoprazole.
 COGENT study: omeprazole vs placebo
 No difference cardiovascular events HR 0.99
[0.68-1.44] but obvious benefit in GIB

88. Clopidogrel and PPI
Bhatt DL, COGENT Investigators. Clopidogrel with or
without omeprazole in coronary artery disease. N Engl J
Med. 2010 Nov 11;363(20):1909-17. Epub 2010 Oct 6.

89. Prasugrel
 Prodrug
 Active metabolite is an irreversible
inhibitor of the platelet P2Y12 receptor.
 CYP2C19 is not the major enzyme 
 Decrease interaction with PPI
 Can be use in clopidogrel hyporesponders

90. ADP antagonist

91. Prasugrel
 TRITON-TIMI 38 trial
 13,608 pts with ACS (10,074 with
UA/NSTEMI) in whom PCI was planned.
 Loading 60 mg  10 mg daily
 Compared to clopidogrel 300  75 mg
 Reduce cardiovascular death, MI, and
stroke by 19% HR 0.81 [0.73-0.90]
 Decrease in stent thrombosis by 52% HR
0.48 p<0.0001

92. Prasugrel

93. Prasugrel
 TRITON-TIMI 38 trial
 More common in serious bleeding
 Risk of bleeding was especially higher in
○ Elderly (>75 yo)
○ Body weight < 60 kg
 Prasugrel is contraindicated in patient with
history of stroke or TIA.
 Prasugrel use should be strictly followed
the study protocol of TRITON-TIMI 38
design.
 Diagnostic catheterization first  planned PCI

94. Ticagrelor
 Non-thienopyridine
 Not require P450 for activation
 Reversibly block P2Y12 platelet receptor
 Ticagrelor and its active metabolite are
excreted into the bile.
 Rapid onset (30 mins)
 Shorter half-life

95. Ticagrelor
 PLATO trial
 18,624 pts;15,381 (62%) had UA/NSTEMI
 Compare Ticagrelor (90 mg BID) with
Clopidogrel (300 or 600  75 mg daily)
 16% Reduction in composite cardiovascular
death, MI, and stroke
 22% Reduction in total mortality

96. Ticagrelor

97. Ticagrelor
 PLATO trial
 No difference in total major bleeding but
significantly higher non-CABG major
bleeding
 Should be started at ER
 If necessary, it could be stopped and
CABG could be carried out 48-72 hrs
later.

98. Glycoprotein IIb/IIIa
inhibitors
 Abciximab (ReoPro) mAb – only prior
PCI
 Eptifibatide (Integrilin)
 Tirofiban (Aggrastat)
 Bind GP IIb/IIIa (αIIbβ3) thus prevent
platelet aggregation caused by all types
of stimuli.

99. Glycoprotein IIb/IIIa
inhibitors
 Intravenous bolus followed by
continuous infusion
 Receptor blocking activity and
associated bleeding risk subside
promptly after discontinuation.
 Several trials confirm the benefit for
cardiovascular death, MI
 Also benefit even on the background of
clopidogrel pretreatment

100. Glycoprotein IIb/IIIa
inhibitors
 Abciximab in UA/NSTEMI pts whom
early conservative strategy was planned
 no benefit and higher early mortality

101. Glycoprotein IIb/IIIa
inhibitors
 Timing of GP IIb/IIIa inhibition
 Starting at the time of presentation or
 Use just before or during PCI
 No difference in benefit
 Risk of major bleeding is higher with
longer infusion group. [EARLY ACS trial]

102. Other antiplatelets

103. Early hospital care antiplatelet
therapy
 Pts with definite UA/NSTEMI at medium
or high risk, initial invasive strategy 
ASA plus one of the following
 Before PCI
○ Clopidogrel (Class I, LOE B)
○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)
 At PCI
○ Clopidogrel if not started
○ Prasugrel (Class I, LOE B)
○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)

104. Early hospital care antiplatelet
therapy
 Pts with initial conservative strategy
 Clopidogrel loading dose followed by daily
maintenance dose [added to ASA and
anticoagulant therapy]
 Administered for at least 1 month
 Ideally up to 1 year (Class I, LOE B)

105. Early hospital care antiplatelet
therapy
 Loading dose of thienopyridines:
 Clopidogrel 300-600 mg as early as possible
before or at the time of PCI (Class I, LOE A)
 Prasugrel 60 mg no later than 1 hr after PCI
once coronary anatomy is defined, decide to
do PCI (Class I, LOE B)
 Maintenance dose at least 12 months
 Clopidogrel 75 mg daily
 Prasugrel 10 mg daily (Class I, LOE B)

106. Early hospital care antiplatelet
therapy
 UA/NSTEMI, early invasive;
 Clopidogrel 600 mg loading dose
 Followed by 150 mg daily for 6 days
 Then 75 mg daily
 In patient not high risk of bleeding (Class IIb,
LOE B)

107. Anticoagulants
 Heparin
 Low-molecular-weight heparin
 Fondaparinux
 Direct thrombin inhibitors
 Direct Xa inhibitors

108. Heparin
 Activating Antithrombin (previously
known as antithrombin III)
 Accelerate the inhibition of Thrombin
and FXa

109. Heparin

110. Heparin
 Unfractionated heparin (UFH) has been
a cornerstone of therapy for patients
with UA/NSTEMI.
 Goal aPTT of 50-75 sec or 1.5-2.5x
 33% reduction in death or MI comparing
UFH+ASA vs ASA alone

111. Low-Molecular-Weight Heparin
 Compare to UFH
 LMWH has greater anti-FXa activity  more
effective in decreasing synthesis of thrombin
 Lower rate of thrombocytopenia
 Higher bioavailability  subcut admin
 Less binding to plasma protein  more
consistent effect  no need for monitoring aPTT
 In case of bleeding, reversal of protamine is less
effective.
 Need renal adjustment

112. Low-Molecular-Weight Heparin

113. Low-Molecular-Weight Heparin
 LMWH was found to be non-inferior to
UFH.
 Enoxaparin provides significant benefit
over UFH in patients with UA/NSTEMI
who are managed conservatively and
receive at least 48 hrs of anticoagulation
but not in patients managed invasively.

114. Fondaparinux
 Synthetic analogue of the antithrombin-
binding sequence found in heparin and
LMWH.
 Indirectly inhibit FXa via antithrombin

115. Fondaparinux
 OASIS-5 trial
 20,078 pts with high-risk UA/NSTEMI
 Low dose fondaparinux (2.5 mg sc daily) vs
standard dose enoxaparin
 No difference in 9-day death, MI
 Lower 30-day mortality (2.9% vs 3.5%)
 Significantly reduce the rate of major
bleeding
 3x increase in catheter related thrombi

116. Direct thrombin inhibitors
 Univalent DTI
 Agatroban
 Apixaban
 Dabigatran
 Bivalent DTI
 Hirudin (leech)
 Lepirudin
 Bivalirudin (Angiomax)

117. Direct thrombin inhibitors
 Not require antithrombin
 Able to inhibit clot-bound thrombin
 Not interact with plasma protein
 Not cause thrombocytopenia
 FDA approved for treatment of HIT
(lepirudin and agatroban)
 Recent FDA approval of bivalirudin for
PCI (but not approved for HIT).

118. Bivalirudin
 Angiomax
 Binds reversibly to thrombin, cleaved by
thrombin
 No need to monitor ACT except in case of
renal insufficiency
 ACUITY trial
 13,819 pts with UA/NSTEMI, managed with
early invasive strategy
 UFH or enoxaparin / GPIIb/IIIa / bivalirudin
 No difference in efficacy (death, MI)
 Lower rate of bleeding in bivalirudin alone

119. Additional Management of
antiplatelet and anticoagulation
 UA/NSTEMI; initial conservative; low
risk stress test
 Indefinite ASA (Class I, LOE A)
 Clopidogrel at least 1 month, ideally 1 yr
(Class I, LOE B)
 UFH for 48 hrs (Class I, LOE A)
 Enoxaparin or Fondaparinux for the duration
of hospitalization, up to 8 days, then
discontinue.

120. Unstable angina
and Non-ST Elevation Myocardial Infarction

121. Treatment Strategies
 Early invasive strategy
 Conservative approach

122. Treatment Strategies
 Early invasive strategy
 Routine early cardiac catheterization
followed by PCI, CABG, or continuing
medical therapy
 Conservative approach
 Initial medical management and
catheterization reserved for patients with
recurrent ischemia either at rest or on a non-
invasive test

123. Treatment Strategies
 To date, comparisons of these 2
strategies have been studied in 10
randomized trials.
 4 trials – no difference
 6 trials – favor invasive strategies

124. Treatment Strategies

125. Indications for invasive vs
conservative management
 Early invasive strategy has been shown
to benefit in patients with
 ST-segment changes
 Positive troponin
 Recurrent ischemia
 Evidence of CHF
 All men and high-risk women

128. Initial invasive vs
initial conservative
 Early invasive strategy is indicated in
patients with
 Refractory angina
 Hemodynamic or electrical instability (Class I,
LOE B)
 Elevated risk for clinical events* (Class I, LOE
A)

130. Diagnosis of UA/NSTEMI is Likely or Definite
ASA (Class I, LOE: A)
Clopidogrel if ASA intolerant (Class I, LOE: B)
Select Management Strategy
Initial Conservative Strategy or Unknown Invasive Strategy†
Initiate anticoagulant therapy (Class I, LOE: A)
Acceptable options include
• Enoxaparin or UFH (Class I, LOE: A)
• Fondaparinux (Class I, LOE: B)*
• Enoxaparin or fondaparinux preferred over UFH
(Class IIa, LOE: B)
Initiate clopidogrel (Class I, LOE: B)
Initiate anticoagulant therapy (Class I, LOE: A)*
Acceptable options include
• Enoxaparin or UFH (Class I, LOE: A)
• Bivalirudin (Class I, LOE: B)
CABG:
Maintenance ASA
(Class I, LOE: A)
Medical
Therapy: D/C
GP IIb/IIIa
inhibitors if
begun and give
clopidogrel per
conservative
strategy
Precatheterization: Add second antiplatelet agent (Class I, LOE: A)‡
• Clopidogrel (Class I, LOE: B) or
• GP IIb/IIIa inhibitor (Class I, LOE: A)
• (IV eptifibatide or tirofiban preferred)
Next step per triage decision at angiography
PCI: Class I:
• Clopidogrel (if not begun
precatheterization) (LOE: A) or
• Prasugrel (LOE: B) or
• Selectively, a GP IIb/IIIa inhibitor (if not
begun precatheterization) (LOE: A)
Wright RS, et al. J Am Coll Cardiol. 2011;57(19):1920-59.
*If fondaparinux is used with an invasive
strategy (Class I, LOE: B), it must be
coadministered with another anticoagulant
with Factor IIa activity, i.e., UFH.)
†Timing of invasive strategy generally is
assumed to be 4 to 48 hours. If immediate
angiography is selected, see STEMI
guidelines.
‡Precatheterization triple antiplatelet
therapy (ASA, clopidogrel, GP inhibitors) is
a Class IIb, LOE: B rec for selected high-
risk patients.

131. • Cont aspirin (Class I, LOE: A)
• DC clopidogrel 5 to 7 d prior to
elective CABG (Class I, LOE: B)
• DC IV GP IIb/IIIa 4 h prior to
CABG (Class I, LOE: B)
• Cont UFH (Class I, LOE: B); DC
enoxaparin 12 to 24 h prior to
CABG; DC fondaparinux 24 h
prior to CABG; DC bivalirudin 3 h
prior to CABG. Dose with UFH
per institutional practice (Class I,
LOE: B)
• Cont aspirin (Class I, LOE
A)
• LD of clopidogrel if not given
pre angio (Class I, LOE: A)
&
• IV GP IIb/IIIa if not started
pre angio (Class I, LOE: A)
• DC ACT after PCI for
uncomplicated cases
(Class I, LOE: B)
• Cont aspirin (Class I, LOE: A)
• LD of clopidogrel if not
given pre angio (Class I, LOE A)*
• DC IV GP IIb/IIIa after
at least 12 h if started pre angio
(Class I, LOE: B)
• Cont IV UFH for at least 48 h (Class
I, LOE: A) or enoxaparin or
fondaparinux for dur of hosp (LOE: A);
either DC bivalirudin or cont at a dose
of 0.25 mg/kg/hr for up to 72 h at
physician„s discretion (Class I, LOE:
B)
Antiplatelet
and ACT at
physician‟s
discretion
(Class I,
LOE: C)
No
significant
obstructive
CAD on
angiography
CAD on angiography
Medical therapyPCICABG
Select Post Angiography Management Strategy
Dx Angiography
Management after Diagnostic Angiography in
Patients with UA/NSTEMI
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 9. ACT = anticoagulation therapy;
LOE = level of evidence.
G
H
I
J
F

132. Cardiac cath
CAD No
Discharge from
protocol
Yes
Left main disease Yes CABG
No
1- or 2-
Vessel
Disease
3- or 2-vessel disease with
proximal LAD involvement
LV dysfunction or
treated diabetes*
No
PCI or
CABG
Medial
Therapy,
PCI or
CABG
Yes CABG
*There is conflicting information about these patients.
Most consider CABG to be preferable to PCI.
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157,
Figure 20.
Revascularization
Strategy in UA/NSTEMI

133. Other therapies
 Inhibition of Renin-Angiotensin-
Aldosterone System
 Angiotensin-converting enzyme inhibitors
 Angiotensin receptor blockers
 Lipid-lowering therapy
 Hydroxymethylglutaryl coA reductase
inhibitors (statins)

134. ACEI/ARB
 Large trials have shown a 0.5% absolute
mortality benefit of early ACEI (within 24
hours) in acute MI.
 No benefit in patients without ST
elevation. [ISIS-4]
 Long-term use prevents ischemic events
and mortality.
 ARB can be used in pts who cannot
tolerate ACEI.

135. ACEI/ARB
 An ACE inhibitor should be administered
orally within the first 24 h to UA/NSTEMI
patients with
 Pulmonary congestion or
 LV ejection fraction (LVEF) less than or equal to
0.40
 Not or known contraindications (class I, LOE A)
 ARB can be used instead in pts who are
intolerant to ACEI. (class I, LOE A)
 ACE inhibitor (or ARB if not tolerate ACEI)
is reasonable in pts without LV dysfunction.
(class IIa, LOE A)

136. Lipid-lowering therapy
 Long-term treatment with statin has
shown benefit in pts after acute MI and
UA/NSTEMI.
 PROVE IT-TIMI 22
 Intensive lipid-lowering therapy with
Atorvastatin 80 mg resulted in 16%
reduction in MI, death or rehospitalization for
ACS compared with moderate dose of
pravastatin (40 mg).
 Suggest Early initiation of statin.

139. Unstable angina
and Non-ST Elevation Myocardial Infarction

140. Long-term secondary
prevention
 Six classes of therapies that have
improved outcomes after UA/NSTEMI in
large randomized trials:
 Intensive LDL-C reduction with high dose statins
 ACEI or ARB
 Beta blocker
 Low dose ASA plus a P2Y12 inhibitor for at least
a year
 Smoking cessation programs
 Exercise-based cardiac rehabilitation

141. Long-Term Antithrombotic Therapy at Hospital
Discharge after UA/NSTEMI
Medical Therapy
without Stent
Bare Metal
Stent Group
Drug Eluting
Stent Group
aspirin 162 to 325 mg/d for at
least 1 month, then 75 to 162
mg/d indefinitely (Class I, LOE: A)
&
Clopidogrel 75 mg/d for at least 1
month and up to 1 year
(Class I, LOE:B)
Add: Warfarin (INR 2.0 to 2.5)
(Class IIb, LOE: B)
Continue with dual antiplatelet
therapy as above
Ye
s
No
Indication for
Anticoagulation?
aspirin 75 to 162 mg/d
indefinitely (Class I, LOE: A)
&
Clopidogrel 75 mg/d at least 1
month (Class I, LOE: A) and
up to 1 year (Class I, LOE: B)
aspirin 162 to 325 mg/d for at
least 3 to 6 months, then 75
to 162 mg/d indefinitely
(Class I, LOE: A)
&
Clopidogrel 75 mg/d for at
least 1 year (Class I, LOE: B)
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.
UA/NSTEMI
Patient Groups at
Discharge

142. Statins
 Statins should be given in pts post-
UA/NSTEMI before discharge,
regardless of baseline LDL-C. (class I,
LOE A)

143. Unstable angina
and Non-ST Elevation Myocardial Infarction

144. ESC 2011 vs ACC/AHA
2011
 Antiplatelets (Class I)
 Ticagrelor (180  90 mg BID) for all mod-
high risk regardless of treatment strategy.
 Prasugrel (60  10 mg daily) is
recommended for P2Y12 naïve patients
(esp DM) in whom coronary anatomy is
known.
 Clopidogrel (300 (or 600 if invasive)  75
mg daily) is recommended for pts who
cannot receive ticagrelor or prasugrel.

145. ESC 2011 vs ACC/AHA
2011
 Anticoagulants (Class I)
 Fondaparinux (2.5 mg sc daily) is
recommended as having the most
favourable efficacy-safety profile.
○ Single bolus UFH at PCI
 Enoxaparin (1mg/kg BID) is recommended
when fondaparinux is not available.

146. ESC 2011 vs ACC/AHA 2011
Indication for invasive strategy

147. Key Reference
 Bonow, RO. Braunwald’s Heart Disease: A textbook
of cardiovascular medicine: Chapter 56 Unstable
angina and Non-ST elevation myocardial infarction.
9th edition. Mar 2011.
 Wright RS, et al. 2011 ACCF/AHA focused update
incorporated into the ACC/AHA2007 Guidelines for
the Management of Patients with Unstable
Angina/Non-ST-Elevation Myocardial Infarction. J Am
Coll Cardiol. 2011 May 10;57(19):e215-367.
 Updated ESC Guidelines for managing patients with
suspected non-ST-elevation acute coronary
syndromes. Eur Heart J. 2011 Dec;32(23):2909-10.