Antithrombin therapy

2
Antithrombotic Agents
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and extension
Thrombolytic agents:
dissolve existing thrombi

1. Vascular Phase
2. Platelet Phase
3. Coagulation Phase
4. Fibrinolytic Phase

1. Vascular Phase
 Vascular Conductance
 Exposure to tissues activate tissue
factor and initiate coagulation
Tissue Factor

2. Platelet phase
 Blood vessel wall (endothelial cells) prevent platelet
adhesion & aggregation
 Platelets contain receptors for fibrinogen and von Willebrand
factor.
 After vessel injury: Platelets adhere & aggregate
 Release permeability increasing factors (e.g.
vascular permeability factor, VPF)
 Loose their membrane & form a viscous plug

3. Coagulation Phase
 2 major pathways
 Intrinsic pathway
 Extrinsic pathway
 Both converge at a common point
 Clotting factors:
13 soluble
Biosynthesis is dependent on Vitamin K1& K2
Most are proteases
Normally inactive & sequentially activated

Intrinsic
Pathway
 All clotting
factors are
within the blood
vessels
 Clotting: slower
 aPTT
Extrinsic Pathway
 Initiating factor is
outside the blood
vessels: tissue
factor
 Clotting: faster in
Seconds
 PT

Thrombi
Arterial
 Occur in areas of rapid
flow (arteries)
 In response to an injured
or abnormal vessel wall
 White
 Composed:
primarily of platelets, also
fibrin & occasional
leukocytes
 Associated with
MI
Stroke
ischemia
Venous
•Occur primarily in the venous
circulation
•In response to venous stasis or
vascular injury
•Red
•Composed
almost entirely of fibrin & erythrocytes
•Associated with
Congestive Heart Failure, Cancer
Surgery.

4. Fibrinolysis
Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to Plasmin
(active form)
Plasmin breaks down fibrin clots

Drug Class Prototype Action Effect
1. Anticoagulant
Heparin Inactivation of clotting
factors
Prevent DVT
Oral Warfarin Decrease synthesis of
clotting factors
Prevent DVT
2. Antiplatelet Aspirin Decrease platelet
aggregation
Prevent arterial
thrombosis
3. Thrombolytic Streptokinase Fibinolysis Breakdown of
thrombi
Deep Vein Thrombosis
Parenteral

13
Antithrombotic Agents

Plaque
Fissure or
Rupture
Platelet
Aggregation
Platelet
Activation
Platelet
Adhesion
Thrombotic
Occlusion

Sites of Anticoagulant Drug Action
Tissue factor
Plasma clotting
cascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Platelet activation
Collagen
Thromboxane A2
ADP
AT
AT
Aspirin
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor
Eptifibatide
Abciximab
Tirofiban
Bivalirudin
Factor
Xa
Heparin
Enoxaparin
Fibrinolytics
Fondaparinux
AT
Anticoagulation Antiplatelet
VorapaxarDabigatran

Prevention of bleeding just as
important as prevention of ischemia:
Safety
Efficacy

Platelet Inhibition Related to the
Risk of Ischemic and Bleeding Events
RiskofAnyEvent
Ferreiro JL et al. Thromb Haemost. 2010;103:1-8.
High risk of
ischemic events
RiskofAnyEvent
Inhibition of platelet aggregation
“Sweet spot”
High risk of
bleeding events
– +
Ischemic risk Bleeding risk

19
Different mechanisms of antiplatelet drugs
1. COX-1 inhibitors: ASA, Omega 3
2. Phosphodiesterase inhibitors
Dipyridamole, Cilostazol
3. ADP-P2Y12 interaction blokers
Ticlopidine, Clopidogrel, Prasugrel, Cangrelor,
Ticagelor
4. GP IIb/IIIa blokers: abciximab
5. Thrombin receptor antagonists: Vorapaxar

Adapted from: Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Desai NR, Bhatt DL. JACC Cardiovasc Interv. 2010;3:571-583.
Antiplatelet Agents
Glycoprotein IIb/IIIa Inhibitors:
abciximab
eptifibatide
tirofiban
PDE3 Inhibitors:
cilostazol
dipyridamole
Fibrinogen
TXA2
ThrombinADP
PGE1
P2Y12 ADP Receptor Antagonists: cangrelor
clopidogrel
elinogrel
prasugrel
ticagrelor
ticlopidine
Thrombin PAR-1 Antagonists:
E5555
vorapaxar
Thromboxane
Inhibitors:
aspirin
ridogrel
S18886
↑cAMP
PDE
GMP
GPIIb/IIIa
activiation
P2Y12
AA TXA2
COX
aspirin+
–
ADP=Adenosine diphosphate, COX=Cyclooxygenase,
TXA2=Thromboxane A2

Aspirin: some background
 Patented by Bayer in 1893
 One of the oldest drugs
 One of the most consumed drugs
(Production in the US is 10 million
Kg/year)
Synthesis of Aspirin

Pharmacokinetics
 Blocks pain impulses in the CNS
 Peripheral blood vessel dilator
 Fever Reducer
 Decreases platelet aggregation
 Atheromatous patches inside vessels allow platelets
to aggregate.
 Aspirin decreases the “stickiness” of platelets by
blocking thromboxane A2 which aggregates platelets
and constricts arteries.

23
Aspirin: Mechanism of Action
Membrane Phospholipids
Arachadonic Acid
Prostaglandin H2
COX-1
Thromboxane A2
 Platelet Aggregation
Vasoconstriction
Prostacyclin
 Platelet Aggregation
Vasodilation
Aspirin

Contraindications ASA
 Trauma (ABSOLUTE)
 Aspirin Allergy (ABSOLUTE)
 GI bleeding (relative, unless actively bleeding)
 Active ulcer disease (relative)
 Hemorrhagic stroke/aneurism
 Bleeding disorders (relative)
 Chest pain suggestive of aortic dissection
 History of asthma exacerbation from ASA
 Children with flu-like symptoms/<13 years of age

25
Thienopyridine: Mechanism of Action
ADP / ATP
P2Y1
P2X1 P2Y12
Gi2 coupled
Gq coupled
Ca2+ Ca2+ cAMP
Platelet shape change
Transient aggregation
No effect on
fibrinogen
receptor
Cation influx
Calcium
mobilization
Fibrinogen receptor
activation
Thromboxane A2 generation
Sustained Aggregation Response
Savi P et al. Biochem Biophys Res Commun 2001;
283:379–83 and Ferguson JJ. The Physiology of
Normal Platelet Function. In: Ferguson JJ, Chronos N,
Harrington RA (Eds). Antiplatelet Therapy in Clinical
Practice. London: Martin Dunitz; 2000: pp.15–35
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor
Optical aggregometry & VerifyNow

27
Antiplatelet Therapy: Common Oral Agents
Acetylsalicylic acid
(ASA)
Clopidogrel
bisulfate*
Ticlopidine
hydrochloride*
Trade Name Aspirin Plavix® Ticlid®
Class Salicylate Thienopyridine Thienopyridine
Formulation Active Drug Pro-Drug Active Drug
Maintenance Dose 75-325 mg daily 75 mg daily 250 mg twice daily
Major Bleeding
Risk (%)
2-3%1 1-4% alone2,3
3-5% w/ ASA4
1% alone5
2-6% w/ ASA6,7
1Topol EJ et al. Circulation 2003;108:399-406
2Diener HC et al. Lancet 2004;364;331-7
3Plavix® package insert. www.sanofi-synthelabo.us
4Peters RJ et al. Circulation 2003;108:1682-7
5Hass WK. NEJM 1989;321:501-7
6Urban P. Circulation 1998;98:2126-32
7Ticlid® package insert. www.rocheusa.com
*Clopidogrel is generally given preference over
Ticlopidine because of a superior safety profile

28
Thienopyridines
• Plavix® (Clopidogrel) 75mg daily
• Efient® (Prasugrel) 10mg daily
• Brilinta® (Ticagrelor) 90mg daily
• Efient® and Brilinta® are “newer”
thienopyridines, indication restricted to
acute myocardial infarction in patients
undergoing PCI (alternative to Plavix)

Cilostazol
Drug Class: Phosphodiesterase III
inhibitor derivative
Approved: January 1999
Dosing: 100 mg bid
Pharmacologic Platelet aggregation inhibitor
Properties: Vasodilation
 HDL-cholesterol (10%)
 Triglycerides (15%)
Inhibits smooth muscle cell
proliferation in vitro

Medications for Patients With PAD
Therapeutic Goal
Drug
To Reduce
Ischemic
Events
To Improve
Claudication
Symptoms
Clopidogrel Yes No
(Plavix®
)
Cilostazol No Yes
(Pletal®
)

Yusuf S et al. Circulation 2003;107:966-972
CURE: Very Early Efficacy of
Clopidogrel in NSTE ACS
Hours After Randomization
0.0
0.005
0.010
0.015
0.020
0.025
0 2 4 6 8 10 12 14 16 18 20 22 24
P=.003
Placebo
+ Aspirin
(n=6303)
Clopidogrel
+ Aspirin
(n=6259)
34%
Relative
Risk
Reduction
CV Death, MI, Stroke, Severe Ischemia
Within First 24 Hours
CumulativeHazardRate

32
Clopidogrel Evidence: Secondary Prevention
Clopidogrel versus Aspirin in Patients at Risk of Ischemic
Events (CAPRIE) Trial
Months Treated
0
1
2
3
5
3 6 9 12 15 18 21 24 27 30 33 36
Aspirin
Clopidogrel
4
P = 0.008
CAPRIE Steering Committee. Lancet 1996;348:1329-39
CVA=Cerebrovascular accident, MI=Myocardial
infarction, PAD=Peripheral arterial disease
19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin
(325 mg) or clopidogrel (75 mg) for 2 years
Clopidogrel provides slightly greater risk reduction

33
Clopidogrel Evidence: Secondary Prevention
Clopidogrel in Unstable Angina to Prevent Recurrent Events
(CURE) Trial
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
3 6 90 12
Rateofdeath,
myocardial
infarction,orstroke
P<0.001
Months of Follow Up
The CURE Trial Investigators. NEJM 2001;345:494-502
NSTE-ACS=Non ST-segment elevation acute
coronary syndrome
Aspirin + Clopidogrel
Aspirin + Placebo
12,562 patients with a NSTE-ACS randomized to daily aspirin (75-325 mg)
or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg)
for 9 months
Dual antiplatelet therapy is more efficacious in NSTE-ACS

Evolution of Antiplatelet Therapy in ACS
Placebo APTC CURE TRITON-TIMI 38
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher
IPA
ASA
ASA + Clopidogrel
ASA +
Prasugrel- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction
in
Ischemic
Events
Increase
in
Major
Bleeds
APTC. BMJ. 1994;308:81-106.
Mehta SR et al. Lancet. 2001;358:527-533.

Adjunctive Antithrombotic Therapy to Support
Reperfusion With Fibrinolytic Therapy

Adjunctive Antithrombotic Therapy to Support PCI
After Fibrinolytic Therapy

Adjunctive Antithrombotic Therapy to Support PCI
After Fibrinolytic Therapy (cont.)
*Balloon angioplasty without stent placement may be used in selected patients. It might be reasonable to
provide P2Y12 inhibitor therapy to patients with STEMI undergoing balloon angioplasty after fibrinolysis alone
according to the recommendations listed for BMS. (Level of Evidence: C)

Therapy for the Metabolic Syndrome
(NCEP- Adult Treatment Panel III)
 Reducing weight and increasing physical activity
 Lowering Triglycerides, raising HDL-c
 Treating hypertension
 Aspirin

Recommendations:
Antiplatelet Agents (1)
• Consider aspirin therapy (75–162 mg/day) (C)
– As a primary prevention strategy in those with type 1 or type 2
diabetes at increased cardiovascular risk (10-year risk >10%)
– Includes most men >50 years of age or women >60 years of
age who have at least one additional major risk factor
• Family history of CVD
• Hypertension
• Smoking
• Dyslipidemia
• Albuminuria
ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32.

Recommendations:
• Aspirin should not be recommended for
CVD prevention for adults with diabetes at
low CVD risk, since potential adverse
effects from bleeding likely offset potential
benefits (C)
• 10-year CVD risk <5%: men <50 and women
<60 years of age with no major additional CVD
risk factors
• In patients in these age groups with
multiple other risk factors (10-year risk
5–10%), clinical judgment is required (E)

Recommendations:
• Use aspirin therapy (75–162 mg/day)
– Secondary prevention strategy in those with diabetes with
a history of CVD (A)
• For patients with CVD and documented aspirin allergy
– Clopidogrel (75 mg/day) should be used (B)
• Combination therapy with ASA (75–162 mg/day) and
clopidogrel (75 mg/day)
– Reasonable for up to a year after an acute coronary
syndrome (B)

Clinical Assessment
Prehospital emergency medical system (EMS)
providers should administer 162 to 325 mg of
aspirin (chewed) to chest pain patients
suspected of having ACS unless contraindicated
or already taken by the patient. Although some
trials have used enteric-coated aspirin for initial
dosing, more rapid buccal absorption occurs
with non–enteric-coated formulations.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Modified
2012

Antiplatelet Therapy
Aspirin should be administered to UA/NSTEMI
patients as soon as possible after hospital
presentation and continued indefinitely in
patients who tolerate it.
A loading dose followed by daily maintenance
dose of either clopidogrel (Level of Evidence:
B), prasugrel (in PCI-treated patients) (Level of
Evidence: C), or ticagrelor (Level of Evidence:
C) should be administered to UA/NSTEMI
patients who are unable to take aspirin because
of hypersensitivity or major gastrointesinal
intolerance.
Modified
2012
Modified
2012
See
recommendation
for LOE

Patients with definite UA/NSTEMI at medium or high risk and in
whom an initial invasive strategy is selected should receive dual
antiplatelet therapy on presentation. (Level of Evidence: A) Aspirin
should be initiated on presentation. (Level of Evidence: A) The
choice of a second antiplatelet therapy to be added to aspirin on
presentation includes 1 of the following (note that there are no data
for therapy with 2 concurrent P2Y12 receptor inhibitors, and this is
not recommended in the case of aspirin allergy):
Before PCI:
•Clopidogrel (Level of Evidence: B); or
•Ticagrelor (Level of Evidence: B); or
•An IV GP IIb/IIIa inhibitor. (Level of Evidence: A) IV eptifibatide
and tirofiban are the preferred GP IIb/IIIa inhibitors. (Level of
Evidence: B)
At the time of PCI:
•Clopidogrel if not started before PCI (Level of Evidence: A); or
•Prasugrel (Level of Evidence: B); or Ticagrelor† (Level of
Evidence: B); or An IV GP IIb/IIIa inhibitor. (Level of Evidence: A)
Modified
2012
See
recommendation
for LOE

Initial Conservative Strategy:
A loading dose of P2Y12 receptor inhibitor therapy is
recommended for UA/NSTEMI patients for whom PCI is
planned. One of the following regimens should be used:
a.Clopidogrel 600 mg should be given as early as
possible before or at the time of PCI (Level of
Evidence: B) or
b.Prasugrel 60 mg should be given promptly and no later
than 1 hour after PCI once coronary anatomy is defined
and a decision is made to proceed with PCI (Level of
Evidence: B) or
c.Ticagrelor 180 mg should be given as early as possible
before or at the time of PCI. (Level of Evidence: B)
Modified
2012
See
recommendation
for LOE

Antiplatelet therapy
Aspirin : as soon as possible (165-325 mg)
- (non enteric formulation orally or chewed).
-Continued indefinitely(75-162mg/d ) in pts who tolerate it.
Clopidogrel :
- loading dose -300mg
- daily maintenance dose 75mg
- Continued for at least 1 month and ideally up to 1 year.
class 1

From: Clopidogrel and Proton Pump Inhibitors: Influence of Pharmacological Interactions on Clinical
Outcomes and Mechanistic Explanations
J Am Coll Cardiol Intv. 2011;4(4):365-380. doi:10.1016/j.jcin.2010.12.009
Clopidogrel Metabolism and Sites of Drug-Drug Interactions and Genetic Polymorphisms
Clopidogrel response variability is a pharmacokinetic problem primarily influenced by cytochrome P450 (CYP) isoenzyme activity in
the generation of the active metabolite. Clopidogrel absorption may be affected by polymorphism of the ABCB1 gene. The activity of
the hepatic cytochrome isoenzymes are influenced by drug-drug interactions (DDIs), single nucleotide polymorphisms (SNPs), and
other factors such as smoking and caffeine consumption.

Omeprazole Metabolism, Mechanism of Action, and Sites of Drug-Drug Interactions and Genetic Polymorphisms
After absorption, omeprazole undergoes activation (protonation) and the activated cyclic sulfonamide irreversibly inhibits H+/K+–
adenosine triphosphatase pump activity/gastric secretion. Omeprazole is extensively metabolized by and competitively inhibits CYP2C19
and CYP3A4. The major omeprazole metabolism pathway involves its conversion by CYP2C19 to inactive 5-hydroxyomeprazole that is
metabolized to inactive omeprazole hydroxy sulfonate by CYP3A4 in the second step. However, omeprazole first metabolized by CYP3A4 to
omeprazole sulfonate and further to omeprazole hydroxy sulfonate in the 2C19 loss-of-function allele carriers or subjects treated with drugs
that are mainly metabolized by 2C19 such as clopidogrel, diazepam, and phenytoin. Abbreviations as in Figure 1.

Potential Mechanisms of Drug-Drug Interaction Between Clopidogrel and Omeprazole
Based on pharmacogenomics, pharmacokinetics, and pharmacodynamics data, is it assumed that the major pathways of interaction
between omeprazole and clopidogrel are intestinal ABCB1 transporter and hepatic 2C19 isoenzymes. Abbreviations as in Figure 1.

the FDA recommendation goes far beyond the two drugs studied. Nexium and
Prilosec interfere with Plavix not because they are members of a particularly
powerful class of acid-reducing drugs called proton pump inhibitors or PPIs, but
because they inhibit an enzyme, CYP 2C19, that activates Plavix.
Several other drugs also inhibit CYP 2C19, and the FDA says patients on Plavix
should avoid them as well. These drugs are:
Tagamet (generic name: cimetidine)
Prozac, Sarafem, and Symbyax (generic name: fluoxetine)
Luvox (generic name: fluvoxamine)
Ticlid (generic name: ticlopidine)
Diflucan (generic name: fluconazole)
Nizoral (generic name: ketoconazole)
VFEND (generic name: voriconazole)
Intelence (generic name: etravirine)
Felbatol (generic name: felbamate)

Use of Proton pump inhibitors
Interfere with the metabolism of clopidogrel
-
- Lansoprazole inhibits CYP450 2C19
- Rabeprazole
Omeprazole : significantly decrease the inhibitory effect of
clopidogrel on platelet aggregation.
Pantoprazole lacks inhibition of CYP450 2C19
-- Deleted recommendation 2011

Asperin, please.
Doctor
Take an asperin every day, but before you
swallow it, take it out for a five-mile walk

Other medications for hypertensive patients
Primary prevention
(1) Aspirin: use 75mg daily if patient is aged 50 years with blood pressure
controlled to <150/90 mm Hg and either; target organ damage, diabetes
mellitus, or 10 year risk of cardiovascular disease of 20% (measured by
using the new Joint British Societies’ cardiovascular disease risk chart)
(2) Statin: use sufficient doses to reach targets if patient is aged up to at
least 80 years, with a 10 year risk of cardiovascular disease of 20%
(measured by using the new Joint British Societies’ cardiovascular
disease risk chart) and with total cholesterol concentration 3.5mmol/l
(3) Vitamins—no benefit shown, do not prescribe

Secondary prevention
(including patients with type 2 diabetes)
(1) Aspirin: use for all patients unless contraindicated
(2) Statin: use sufficient doses to reach targets if patient is
aged up to at least 80 years with a total cholesterol
concentration 3.5 mmol/l
(3) Vitamins— no benefit shown, do not prescribe
Other medications for hypertensive patients

Antiplatelet Therapy to Support
Primary PCI for STEMI
Reperfusion at a PCI-Capable Hospital
2013 ACCF/AHA Guideline

Aspirin 162 to 325 mg should be given before primary PCI.
After PCI, aspirin should be continued indefinitely.
I IIa IIb III
I IIa IIb III

A loading dose of a P2Y12 receptor inhibitor should be given as
early as possible or at time of primary PCI to patients with STEMI.
Options include:
• Clopidogrel 600 mg; or
I IIa IIb III
• Prasugrel 60 mg; or
• Ticagrelor 180 mg

P2Y12 inhibitor therapy should be given for 1 year to patients with
STEMI who receive a stent (BMS or DES) during primary PCI
using the following maintenance doses:
• Clopidogrel 75 mg daily; or
I IIa IIb III
• Prasugrel 10 mg daily; or
• Ticagrelor 90 mg twice a day*
*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg
daily.

Metabolism of P2Y12 Receptor
Antagonists
Adapted from: Schomig A. NEJM. 2009;361(11):1108-1111.
Effient (Prasugrel) Product Monograph March 11, 2011 version.
Brilinta (Ticagrelor) Product Monograph May 26, 2011 version.
Plavix (Clopidogrel) Product Monograph May 9, 2011 version.

Properties of P2Y12 Receptor
Antagonists
Clopidogrel Prasugrel Ticagrelor
Requires Metabolic
Activation through
CYP2C19
Yes sensitive to
polymorphisms and drug
interactions
Yes but less sensitive to
polymorphisms and drug
interactions
No
Indications ACS, PCI, PAD, CVD PCI ACS, PCI
Loading/Maintenance
Dosing
600 mg /75 mg OD 60 mg/10 mg OD 180 mg/90 mg BID
Inhibition Irreversible Irreversible Reversible
Efficacy ++
• Further 2% ARR over
ASA monotherapy
+++
• Further 2% ARR over clopidogrel +
ASA
+++
• Further 2% ARR over
clopidogrel + ASA
Bleeding risk + ++ ++
Issues • Rash
4.2% observed in clinical
trials leading to 0.5%
drug discontinuation
• Further increased bleeding risk in:
Prior Stroke / TIA
< 60 Kg
>75 yrs
• Increased fatal bleeding
• Dyspnea
• Ventricular pause
• Hyperuricemia
• Slight increased Cr
ARR – Absolute Risk Reduction. Note: No head to head data between prasugrel and ticagrelor.

It is reasonable to use 81 mg of aspirin per day in preference to
higher maintenance doses after primary PCI.
I IIa IIb III

It is reasonable to start treatment with an intravenous GP IIb/IIIa
receptor antagonist at the time of primary PCI (with or without
stenting or clopidogrel pretreatment) in selected patients with
STEMI who are receiving UFH.
• Double-bolus eptifibatide: 180 mcg/kg IV bolus, then 2
mcg/kg/min; a 2nd 180-mcg/kg bolus is administered 10 min
after the 1st bolus.
• Abciximab: 0.25 mg/kg IV bolus, then 0.125 mcg/kg/min
(maximum 10 mcg/min); or
• High-bolus-dose tirofiban: 25 mcg/kg IV bolus, then 0.15
mcg/kg/min; or
I IIa IIb III
I IIa IIb III
I IIa IIb III

It may be reasonable to administer intravenous GP IIb/IIIa
receptor antagonist in the precatheterization laboratory setting
(e.g., ambulance, ED) to patients with STEMI for whom primary
PCI is intended.
It may be reasonable to administer intracoronary abciximab to
patients with STEMI undergoing primary PCI.
I IIa IIb III
I IIa IIb III
Continuation of a P2Y12 inhibitor beyond 1 year may be
considered in patients undergoing DES placement.
I IIa IIb III

Prasugrel should not be administered to patients with a history of
prior stroke or transient ischemic attack.
I IIa IIb III
Harm

Antiplatelet Agents
GP IIb/IIIa Inhibitors
Fibrinogen
GP IIb/IIIa
Receptor
GP IIb/IIIa
Inhibitors

GP IIb/IIIa inhibitors
 Newer class of molecules
 Only used as infusion before, during and max
72h after PCI in acute coronary syndrome
(mostly STEMI)
 Reopro® (Abciximab)
 Aggrastat® (Tirofiban)
 Integrilin® (Ebtifibatide)
 Platelet function returns to normal 24-48h after
the end of the infusion for Reopro®, a bit faster
for Aggrastat® and Integrilin®
 High risk of bleeding, especially since used
concomitantly to Aspirin and Plavix!
Australian Medicines handbook

Antiplatelet Agents
GP IIb/IIIa Inhibitors (cont.)
 Monoclonal antibody: abciximab
 Natural products — disintegrin family:
RGD containing proteins (from viper venom)
 Synthetic peptides: eptifibatide
 Nonpeptide inhibitors — RGD mimics:
tirofiban, lamifiban, fradafiban
 Oral agents:
xemilofiban, orofiban, lefradafiban,
sibrafiban, roxifiban
Meyer BJ, 1998

Antiplatelet Agents
GP IIb/IIIa Inhibitors (cont.)
 Abciximab, eptifibatide, tirofiban: 35,000
patients studied in ACS and patients
undergoing percutaneous coronary
interventions
 Risk reductions in death/MI/emergency
revascularization up to 50%
 Risk reductions in death/new MI range from
10%-27%
 Patients undergoing interventions and with
ACS (when used with heparin) appear to
benefit

For UA/NSTEMI patients in whom an initial
conservative strategy is selected and who have
recurrent ischemic discomfort with clopidogrel,
aspirin, and anticoagulant therapy, it is
reasonable to add a GP IIb/IIIa antagonist
before diagnostic angiography.

The use of upstream GP IIb/IIIa inhibitors
may be considered in high-risk UA/NSTEMI
patients already receiving aspirin and a
P2Y12 receptor inhibitor (clopidogrel or
ticagrelor) who are selected for an invasive
strategy, such as those with elevated
troponin levels, diabetes, or significant ST-
segment depression, and who are not
otherwise at high risk for bleeding.
Modified
2012

Abciximab should not be administered to
patients in whom PCI is not planned.
In UA/NSTEMI patients who are at low risk
for ischemic events (e.g., TIMI risk score ≤2)
or at high risk of bleeding and who are
already receiving aspirin and a P2Y12
receptor inhibitor, upstream GP IIb/IIIa
inhibitors are not recommended.
No Benefit
Modified
2012

• Vorapaxar:
 First-in-class
 Oral PAR-1
inhibitor
• Metabolism:
 Primarily hepatic
via CYP 3A4
 Terminal half-life:
~126–269 hrs
• Prior trials:
 No increase in
bleeding and
fewer MIs
Background
Chackalamannil S, J Med Chem, 2006
Platelet
PAR-4
TBX A2
TBXA2-R
Thrombin
Anionic
phospholipid
surfaces
GP IIb/IIIa
ADP
P2Y12
PAR-1
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
ASA
Vorapaxar

Target Platelet Receptor
TxA2
Terutroban
vWF
Gp1b ARC1779
ALX-0081
AJW200
Thrombin
PAR-1
Vorapaxar
SCH 205831
Atopaxar
ADP
P2Y12
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Elinogrel

New Target for Antiplatelet Therapy:
Thrombin Receptor Antagonist (TRA)
Thrombin
Xa+Va+II
Thrombus
Fibrinogen
Fibrin
TRA
X

TRA (vorapaxar) program
(29,500 patients)
1o EP: composite of CV
death, MI, stroke and urgent
re-vascularisation
TRA Program
Evaluation of Efficacy and Safety in Acute and Chronic
Atherothrombosis
NSTE-ACS
~12,500 patients
2º prevention
~26,400 patients
Vorapaxar Placebo Vorapaxar Placebo
Follow-up: at 30 days; at 4, 8 and 12 months;
and at 6 months thereafter (1-year minimum)
1o EP: composite of
CV death, MI, stroke, urgent
re-vascularisation and
recurrent ischaemia
with re-hospitalisation
ClinicalTrials.gov Identifier: NCT00527943. ClinicalTrials.gov Identifier: NCT00526474.
TRA-CER TRA2P

Antithrombotic agents: summary
• Antiplatelet agents: Aspirin . This well tested, widely used, and cheap agent
• Ticlopidine and clopidogrel. These antiplatelet agents preferred for prevention of stroke
and acute thrombotic closure after coronary artery stenting.
• Glycoprotein IIb/IIIa receptor blockers, they are often used in acute coronary syndromes:
Abciximab, eptifibatide, tirofiban.
• Thrombin Receptor Antagonist (TRA): Vorapaxar
• Intravenous unfractionated heparin: backbone of anticoagulation in acute myocardial
infarction with or without thrombolysis.
LMWH: is easier to administer than unfractionated heparin
• Direct thrombin inhibitors are more effective than unfractionated heparin in unstable
angina, but carry a higher risk of major bleeding except for bivalirudin .
• Warfarin: slow onset of action over several days.
• Fibrinolytic agents: early stages of acute myocardial infarction

Anticoagulants – historical development
1916 1924 1936 1940 1950s 20061970s 1976 1980s 1990s 2001
Oral
Injection
Spoiled
sweet clover
Dicoumarol
discovered
Warfarin
clinical use
Warfarin / Vitamin K
mechanism
High / low dose
Warfarin / INR
Warfarin
clinical trials
Heparin
discovered
Heparin
clinical use
Continous heparin
infusion/
aPTT
LMWH
discovered
LMWH
clinical trials
Pentasaccharide
clinical trials
Ximelagatran
clinical trials
Dabigatran
Rivaroxaban
Apixaban
AZD0837
2013

Enhances
Antithrombin Activity

Enhances
Warfarin

Enhances
Dabigatran

Oral Anticoagulant Target Sites
Antithrombin
Fibrinogen
Factor II
(Prothrombin)
Fibrin
Factor IIa
(Thrombin)
Factor X
Factor IX Factor VII
Anti-FXa drugs
•Apixaban
•Betrixaban
•Edoxaban
•Rivaroxaban
•LY 517717
•TAK 442
•YM 150
Anti-FIIa drugs
•Dabigatran
•Ximelagatran
•AZD 0837
Factor Xa
VKA drugs
•Tecarfarin
•Warfarin
VIIa
IXa

85
Current Options
Vitamin K Antagonist
Unfractionated Heparin
(UFH)
Low Molecular Weight
Heparin (LMWH)
Direct Thrombin
Inhibitors
Factor Xa Inhibitors
Warfarin
Heparin
Enoxaparin
Bivalirudin
Dabigatran
Argatroban
Fondaparinux
Rivaroxaban
Apixiban

Initial Invasive Strategy:
Anticoagulant Therapy
Anticoagulant therapy should be added to
antiplatelet therapy in UA/NSTEMI patients as
soon as possible after presentation.
•For patients in whom an invasive strategy is
selected, regimens with established efficacy at a
Level of Evidence: A include enoxaparin and
unfractionated heparin (UFH), and those with
established efficacy at a Level of Evidence: B
include bivalirudin and fondaparinux.

Organization to
Assess Strategies for Ischaemic
Syndromes (OASIS-5)
•Fondaparinux (fonda) (2.5 mg/day, n=10,057) vs enox (1.0 mg/kg BID,
n=10,021) in UA/NSTEMI patients
― Enox patients undergoing PCI → UFH if last dose of enox > 6 h
before PCI
•Other meds: aspirin, clopidogrel, GP IIb/IIIa @ investigator discretion
•No ↓ death, MI or refractory ischemia @ 9 d by fonda
― Noninferiority criteria met
•↓ Major bleeding with fonda
•↓ Death @ 30 d and 180 d and ↓ death, MI and stroke @ 180 d with
fonda
•↑ Catheter-assoc thrombus with fonda
Yusuf S, et al. N Engl J Med 2006;354:1464–76.
Also see Section 3.2.5.5 in Anderson JL, et al. J Am Coll Cardiol 2007;50:e1-e157 for detailed discussion of trial results and dosing protocol.

OASIS 5 Cumulative Risk of Death, MI, or
Refractory Ischemia
*p for noninferiority; †p for superiority. Yusuf S, et al. N Engl J Med 2006;354:1464–76.
5.7
4.1
9.0
5.8
2.2
7.3
0
1
2
3
4
5
6
7
8
9
10
OASIS 5 Death, MI, or refractory
ischemia at 9 days
OASIS 5 Major bleeding at 9
days
OASIS 5 Composite primary
outcome and major bleeding at 9 days
Enoxaparin
Fondaparinux
Absolute Risk Reduction -0.1 1.9 1.7
Hazard Ratio 1.01 0.52 0.81
Confidence Interval 0.90–1.13 0.44–0.61 0.73–0.89
p 0.007* < 0.001† < 0.001†

93
Bleeding Risk Assessment Tools
1.ACS – CRUSADE
2. AF – HAS – BLED
3.DVT/PE – Out Patient Bleeding Risk Index
4.DVT- PE – IMPROVE
5. DVT/PE – HEMORR2HAGES

94
Dosage Strength Tablet Color
1mg Pink
2mg Lavender
2.5mg Green
3mg Tan
4mg Blue
5mg Peach
6mg Teal
7.5mg Yellow
10mg White
Warfarin Tablet Identification

CRUSADE Bleeding Score Nomogram
Note: Heart rate is truncated @ <70 bpm;
CrCl: Cockcroft-Gault is truncated @ >90 mL/min; Prior Vascular disease is defined as prior PAD or stroke
Predictor Range Score
Baseline Hematocrit (%) < 31
31-33.9
34-36.9
37-39.9
≥ 40
9
7
3
2
0
Creatinine Clearance (mL/min) ≤ 15
>15-30
>30-60
>60-90
>90-120
>120
39
35
28
17
7
0
Heart rate (bpm) ≤ 70
71-80
81-90
91-100
101-110
111-120
≥ 121
0
1
3
6
8
10
11
Sex Male
Female
0
8
Signs of CHF at presentation No
Yes
0
7
Prior Vascular Disease No
Yes
0
6
Diabetes Mellitus No
Yes
0
6
Systolic blood pressure (mm Hg) ≤ 90
91-100
101-120
121-180
181-200
≥ 201
10
8
5
1
3
5

Risk Quintiles
 Patients were categorized into quintiles of risk
groups based on their CRUSADE Bleeding
Score
Risk N Min Score Max Score Bleeding
Very low 19,486 1 20 3.1%
Low 12,545 21 30 5.5%
Moderate 11,530 31 40 8.6%
High 10,961 41 50 11.9%
Very High 15,210 51 91 19.5%

99
Outpatient Bleeding Risk Index

100
Bleeding Risk Assessment Score for Outpatients on Warfarin
The HAS-BLED Score

Indications of Anticoagulant Therapy
• Treatment & Prevention of Deep Venous Thrombosis
• Pulmonary Emboli
• Prevention of stroke in patients with atrial fibrillation,
artificial heart valves, cardiac thrombus.
• Ischaemic heart disease
• During procedures such as cardiac catheterisation and
apheresis.

YING - YANG PRINCIPLE
• With every approach to reduce thrombosis,
however, there is an accompanying risk of
increasing bleeding complications .
• Conversely, reducing bleeding complications
may increase thrombotic (ischemic) events.

Thrombosis vs Bleeding
• They both increase morbidity and mortality
• Balancing both ends of the spectrum is
essential, and an individualized approach to
therapy is advocated.

Atrial Fibrillation Update 2012
1. Rate control vs. Rhythm control
2. Who requires anticoagulants and
which ones?
3. What is the role of atrial fibrillation
ablation?

Simplified classification
• Paroxysmal→spontaneously terminate <7 days
• Persistent→lasts >7 days and requires
intervention to restore sinus rhythm
• Permanent→sinus rhythm can not be restored
by intervention

Goals of Therapy
1. Relieve symptoms
2. Prevent Stroke
3. Prevent Heart Failure

1.5% in <
60 yrs
23.5% in
> 80 yrs

BRIDGING (if known
thrombus or
thromboembolism):
– IV Heparin
– Enoxaparin
– Dalteparin?
– Tinzaparin?
– Fondaparinux?
MAINTENANCE:
– Warfarin
– Dabigatran
– Aspirin
– Clopidogrel
OTHER:
– Left atrial appendage
closure (surgical or
catheter-based)
Anticoagulation

www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429
The management cascade for patients with AF
ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker;
PUFA = polyunsaturated fatty acid; TE = thrombo-embolism.

Risk factor-based point-based scoring
system - CHA2DS2-VASc
*Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary
cohorts may vary from these estimates.

Use of oral anticoagulation for
stroke prevention in AF
AF = atrial fibrillation; OAC = oral anticoagulant; TIA = transient ischaemic attack.

Approach to thromboprophylaxis in AF
AF = atrial fibrillation; CHA2DS2-VASc = cardiac failure, hypertension, age ≥ 75 (doubled), diabetes, stroke (doubled)-
vascular disease, age 65–74 and sex category (female); INR = international normalized ratio; OAC = oral anticoagulation,
such as a vitamin K antagonist (VKA) adjusted to an intensity range of INR 2.0–3.0 (target 2.5).

Copyright © The American College of Cardiology.
All rights reserved.
From: Practical Management of Anticoagulation in Patients With Atrial Fibrillation
J Am Coll Cardiol. 2015;65(13):1340-1360. doi:10.1016/j.jacc.2015.01.049
Management of Patients with Both AF and Coronary Stents
(A) Patients taking anticoagulants for AF requiring coronary artery stenting. (B) Patients taking DAPT for coronary artery stent who
develop AF. ACS = acute coronary syndrome(s); AF = atrial fibrillation; ASA = aspirin; BMS = bare-metal stent(s); DAPT = dual
antiplatelet therapy; DOAC = direct-acting oral anticoagulant; INR = international normalized ratio; VKA = vitamin K antagonist.

International Normalised Ratio (INR)
Target
INR
(2.0-3.0)
<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.5
0
20
40
60
80
Events/1000patientyears
Intracranial haemorrhage
Ischaemic stroke
The anticoagulant
effect of vitamin K
antagonists are
optimized when
therapeutic doses are
maintained within a
very narrow range
• N Engl J Med 2003; 349: 1019-26.
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
-Narrow Therapeutic Window

AT: antithrombin
Fondaparinux: xa
TL: Weitz JI et al. New Antithrombotic Drugs: antithrombotic therapy and prevention of
thrombosis. Chest 2012; 141: ed 120s- e151s.

New Anticoagulants
TFPI (tifacogin)
Fondaparinux
Idraparinux
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
Betrixaban
TAK 442
Dabigatran
ORAL PARENTERAL
DX-9065a
Xa
IIa
TF/VIIa
X IX
IXa
VIIIa
Va
II
FibrinFibrinogen
AT
APC (drotrecogin alfa)
sTM (ART-123)
Adapted from Weitz & Bates, J Thromb Haemost 2007
TTP889

Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban
Mechanism
of action
Thrombin
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
T1/2 14-17 hours 5-9 hours 12 hours 19-24 hours 6-12 hours
Regimen bid qd, bid bid qd qd
Peak to trough ~7x 12x (qd) 3x-5x ~3x ~3x
Renal
excretion of
absorbed drug
~80% 36%-45% 25%-30% ~15% 35%
Potential
for drug
interactions
P-glycoprotein
inhibitor
CYP3A4
substrate
and
P-glycoprotein
inhibitor
CYP3A4
substrate
and
P-glycoprotein
inhibitor
CYP3A4
substrate
and
P-glycoprotein
inhibitor
Usman MH et al. Curr Treat Options Cardiovasc Med. 2008;10:388-97.
Piccini JP et al. Curr Opin Cardiol. 2010;25:312-20.
Not
substrate
for major
CYPs
Novel Oral Anticoagulants

Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Dabigatran etexilate
110 mg bid
N=6000
Dabigatran etexilate
150 mg bid
N=6000
• Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
• Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
• N Engl J Med 2009; 361 : 1139-51.
-The RE-LY Study
-Study Design

1) Documented atrial fibrillation and
2) One additional risk factor for stroke:
a) History of previous stroke, TIA, or systemic embolism
b) LVEF less than 40%
c) Symptomatic Heart Failure, NYHA Class II or greater
d) Age of 75 years or more
e) Age of 65 years or more and one of the following additional risk
factors: Diabetes mellitus, CAD
or Hypertension
-The RE-LY Study
-Inclusion Criteria
• N Engl J Med 2009; 361 : 1139-51.

0.50 0.75 1.00 1.25 1.50
Dabigatran 110 mg
vs. warfarin
Dabigatran 150 mg
vs. warfarin
Noninferiority
p-value
<0.001
<0.001
Superiority
p-value
0.34
<0.001
Margin=1.46
HR (95% CI)
• N Engl J Med 2009; 361: 1139-51.
-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism

0.01
0.02
0.03
0.05
0.04
Cumulativehazardrates
RR 0.91
(95% CI: 0.74–1.11)
p<0.001 (NI)
p=0.34 (Sup)
RR 0.66
(95% CI: 0.53–0.82)
p<0.001 (NI)
p<0.001 (Sup)
Years
0 0.5 1.0 1.5 2.0 2.5
0.0
Warfarin
Dabigatran etexilate 110 mg
RRR
34%
-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism
• N Engl J Med 2009; 361: 1139-51.

RR 0.40
(95% CI: 0.27–0.60)
p<0.001 (Sup)
RR 0.31
(95% CI: 0.20–0.47)
p<0.001 (Sup)
Cumulativehazardrates
Warfarin
Years
0.0
0.01
0.02
0 0.5 1.0 1.5 2.0 2.5
RRR
60%
RRR
69%
• N Engl J Med 2009; 361: 1139-51.
-The RE-LY Study
-Intracranial Bleeding

RELY
• Dabigatran 110 mg twice daily
– Equal to warfarin in stroke prevention
• Warfarin 1.69%/yr – dabigatran (110mg) 1.53%/yr
– Less bleeding than warfarin
• Warfarin 3.36%/year – dabigatran (110mg) 2.71%/yr
• Dabigatran 150 mg twice daily
– More effective than warfarin in stroke prevention
• Dabigatran (150mg) 1.11%/yr
– Equivalent bleeding to warfarin
less hemorrhagic stroke than warfarin

Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
P-value
110 vs. W
P-value
150 vs. W
Number of patients (n) 6015 6076 6022
Major bleeding 2.71 3.11 3.36 0.003 0.31
- Life threatening
- Non-life threatening
- Gastrointestinal
1.22
1.66
1.12
1.45
1.88
1.51
1.80
1.76
1.02
<0.001
0.56
0.43
0.037
0.47
<0.001
Data represents %/year
-The RE-LY Study
-Major Bleeding in the RE-LY Study
• N Engl J Med 2009; 361: 1139-51.

Less
Bleeding
-The Antithrombotic Therapy In Perspective
Warfarin
1.5 2.0 2.5 3.00.75
0.5
1.5
0.75
Dabigatran
ASA+Clopidogrel
Placebo
Aspirin
More
Bleeding
Less
Strokes
More
Strokes

Treatment Stroke Risk
(/year)
No Therapy 4.5
ASA 3.7
ASA + Clopidogrel 2.8
Warfarin 1.7
Dabigatran 110 1.5
Dabigatran 150 1.1

(/year)
No Therapy 4.5
ASA 3.7
Warfarin 1.7
Dabigatran 110 1.5
Dabigatran 150 1.1
64%

(/year)
No Therapy 4.5
ASA 3.7
Warfarin 1.7
Dabigatran 110 1.5
Dabigatran 150 1.1
34%

(/year)
No Therapy 4.5
ASA 3.7
Warfarin 1.7
Dabigatran 110 1.5
Dabigatran 150 1.1
76%

-The Natural History of Atrial Fibrillation
Cardiovascular Outcomes
(Stroke, Death, Hospitalization)
Sinus Rhythm
Asymptomatic A Fib
Symptomatic A Fib
Paroxysmal
A Fib
Persistent
A Fib
Permanent
A Fib

Dabigatran vs. Warfarin
Noninferiority trial randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive:
1. Fixed doses of dabigatran — 110 mg or 150 mg twice daily in a blinded fashion
2. Adjusted-dose warfarin in an unblinded fashion
The median duration of the follow-up period was 2.0 years.
The primary outcome was stroke or systemic embolism.
Results
Primary outcome
1.69% per year in the warfarin group
1.53% per year in the group that received 110 mg of dabigatran (P<0.001 for noninferiority)
1.11% per year in the group that received 150 mg of dabigatran ( P<0.001 for superiority)
Major bleeding
2.71% per year in the group receiving 110 mg of dabigatran (P=0.003)
3.11% per year in the group receiving 150 mg of dabigatran (P=0.31).
Hemorrhagic stroke
0.12% per year with 110 mg of dabigatran (P<0.001)
0.10% per year with 150 mg of dabigatran (P<0.001).
Mortality rate
3.75% per year with 110 mg of dabigatran (P=0.13)
3.64% per year with 150 mg of dabigatran (P=0.051).
Conclusions
Dabigatran 110 mg had rates of stroke and systemic embolism similar to warfarin with less major hemorrhage.
Dabigatran 150 mg had lower rates of stroke and systemic embolism but similar rates of major hemorrhage.
Stuart J. Connolly and the RE-LY Steering Committee and Investigators NEJM Sept 17, 2009, No. 12, Vol 361: 1139-1151

2012 ACCP Guidelines for Antithrombotic Therapy
in Patients Undergoing Cardioversion for AF
Patient features Recommended antithrombotic therapy
AF of >48 hrs or unknown
duration with elective
cardioversion
Therapeutic anticoagulation (dose-adjusted VKA*, LMWH, or
Dabigatran) for 3 weeks before cardioversion
OR TEE-guided approach with abbreviated anticoagulation
Therapeutic anticoagulation 4 weeks after successful cardioversion
AF of known duration
≤48 hrs with elective
cardioversion
Immediate anticoagulation with IV UFH or LMWH, then therapeutic
anticoagulation (dose-adjusted VKA*, LMWH, or Dabigatran)
4 weeks after successful cardioversion
Urgent cardioversion
for haemodynamically
unstable AF
Parenteral anticoagulation as soon as possible, then therapeutic
anticoagulation (dose-adjusted VKA*, LMWH, or Dabigatran)
4 weeks after successful cardioversion
Cardioversion of atrial
flutter
As for patients undergoing cardioversion for AF
*Target range for international normalized ratio: 2.0–3.0
IV = intravenous; LMWH = low-molecular-weight heparin; TEE = transoeosophageal echocardiography;
UFH= unfractionated heparin; VKA = vitamin K antagonist
You JY et al. Chest 2012;141;e531S–e575S
142
Long-term antithrombotic therapy should follow the risk-based recommendations for AF

(EuropeanMedicinesAgency.Pradaxa.SummaryofProductCharacteristics.
htttp://www.ema.europa.eu/docs/en_GB/document_library)

144
Stroke PreventionStroke
Prevention
Adverse Events
Starting dose 110 vs 150 mg bid ?

Anticoagulation Therapy
 Heparin is used to prevent recurrence of
emboli but has no effect on emboli that
are already present.
 It is administered as an intravenous bolus
of 5,000 to 10,000 units, followed by a
continuous infusion initiated at a dose of
18 U/kg per hour, not to exceed 1,600
U/hour

Anticoagulant therapy should be added to
antiplatelet therapy in UA/NSTEMI patients as
soon as possible after presentation.
•For patients in whom a conservative strategy is
selected, regimens using either enoxaparin* or
UFH (Level of Evidence: A) or fondaparinux
(Level of Evidence: B) have established
efficacy.
•In patients in whom a conservative strategy is
selected and who have an increased risk of
bleeding, fondaparinux is preferable.
*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.

For UA/NSTEMI patients in whom an initial
conservative strategy is selected, enoxaparin* or
fondaparinux is preferable to UFH as
anticoagulant therapy, unless CABG is planned
within 24 h.
*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.

149

PathophysiologyStable Angina
•Progressive
narrowing of coronary
lumen
•Stable fibrous cap
Unstable Angina
•Progressive
narrowing
•Acute worsening of
coronary lumen due
to thrombus
formation
NSTEMI
•Acute worsening of
coronary lumen due to
thrombus formation
•Sub-occlusive/
transient coronary
thrombus with
myocardial necrosis
STEMI
•Minimal prior
narrowing of
coronary lumen
•Acute rupture of thin
fibrous cap
•Occlusive thrombus
formation
•Acute injury pattern
•Myocardial necrosis

Clinical manifestations of arterial
thrombosis
UA/NQMI:
Partially-occlusive thrombus
(primarily platelets)
Intra-plaque
thrombus (platelet
dominated)
Plaque core
ST  MI:
occlusive thrombus (platelets,
red blood cells, and fibrin)
Intra-plaque
thrombus (platelet
dominated)
Plaque core
SUDDEN
DEATH
Adapted from Davies MJ. Circulation. 1990; 82
(supl II): 30-46.

Common thrombolytics regimens for
STEMI1
Initial treatment Co-therapy Contraindications
Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or
D5W or NS over 3060 min heparin x 2448 hrs anistreplase
Alteplase (tPA) 15 mg iv bolus, then iv heparin x 2448 hrs
0.75 mg/kg over 30 min,
then 0.5 mg/kg iv over 60 min
Total dose not over 100 mg
Reteplase (r-PA) 10 U + 10 U iv bolus given iv heparin x 2448 hrs
30 min apart
Tenecteplase Single iv bolus iv heparin x 2448 hrs
(TNK-tPA) 30 mg if <60 kg
35 mg if 60 kg to <70 kg
50 mg if ≥90 kg
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Note: ASA should be given to all patients without contraindications

OASIS-5: PCI Substudy
• ACS pts with cath or PCI during hospitalization (n=20,078)
• Fondaparinux vs enoxaparin (if PCI <6 h from last SC dose, no
additional anticoagulant; if PCI >6 h, additional IV UFH)
• Fondaparinux ↓ major bleeding at day 9 vs. enoxaparin (2.4% vs.
5.1%; p<0.00001); similar ischemic events
• Superior net clinical benefit (death, MI, stroke, major bleeding)
fondaparinux vs enoxaparin (8.2% vs. 10.4%; p=0.004)
• Catheter thrombus ↑ with fondaparinux vs. enoxaparin (0.9% vs. 0.4%)
– Largely prevented by UFH at time of PCI (without ↑ in bleeding)
Mehta SR, et al. JACC 2007;50:1742–51. Revised 2012

Additional Management Considerations
For UA/NSTEMI patients in whom a conservative
strategy is selected and who do not undergo
angiography or stress testing, the instructions
noted below should be followed:
a. Continue aspirin indefinitely. (Level of
Evidence: A)
b. Continue clopidogrel or ticagrelor for up to
12 months. (Level of Evidence: B)
c. Discontinue IV GP IIb/IIIa inhibitor if started
previously. (Level of Evidence: A)
d. Continue UFH for 48 hours (Level of
Evidence: A) or administer enoxaparin (Level
of Evidence: A) or fondaparinux (Level of
Evidence: B) for the duration of hospitalization,
up to 8 days, and then discontinue
anticoagulant therapy.
See a-d for LOE
Modified
2012
Modified
2012

171
Thrombolytic Therapy
• -Thrombolytic therapy (urokinase, strepto-
kinase, alteplase, anistreplase, reteplase)
also may be used in treating
• PE, particularly in patients who are
severely compromised (eg, those who are
hypotensive and have significant
hypoxemia despite oxygen
supplementation).

172

•Age ≥ 65 years
•At least 3 risk factors for CAD
•Prior coronary stenosis of ≥ 50%
•ST-segment deviation on ECG presentation
•At least 2 anginal events in prior 24 hours
•Use of aspirin in prior 7 days
•Elevated serum cardiac biomarkers
Variables Used in the TIMI Risk Score
The TIMI risk score is determined by the sum of the presence of the above 7 variables at admission. 1 point is given for each variable.
Primary coronary stenosis of 50% or more remained relatively insensitive to missing information and remained a significant predictor of
events. Antman EM, et al. JAMA 2000;284:835–42.
TIMI = Thrombolysis in Myocardial Infarction.

TIMI
Risk
Score
All-Cause Mortality, New or Recurrent MI, or Severe
Recurrent Ischemia Requiring Urgent Revascularization
Through 14 Days After Randomization %
0-1 4.7
2 8.3
3 13.2
4 19.9
5 26.2
6-7 40.9
TIMI Risk Score
Reprinted with permission from Antman EM, et al. JAMA 2000;284:835–42. Copyright © 2000, American Medical
Association. All Rights reserved. The TIMI risk calculator is available at www.timi.org.
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Table 8. TIMI = Thrombolysis in Myocardial Infarction.

Variable Odds ratio
Older age 1.7 per 10 y
Killip class 2.0 per class
Systolic BP 1.4 per 20 mm Hg ↑
ST-segment deviation 2.4
Cardiac arrest during presentation 4.3
Serum creatinine level 1.2 per 1-mg/dL ↑
Positive initial cardiac biomarkers 1.6
Heart rate 1.3 per 30-beat/min ↑
GRACE Risk Score
The sum of scores is applied to a reference monogram to determine the corresponding all-cause mortality from hospital
discharge to 6 months. Eagle KA, et al. JAMA 2004;291:2727–33. The GRACE clinical application tool can be found at
www.outcomes-umassmed.org/grace. Also see Figure 4 in Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157.
GRACE = Global Registry of Acute Coronary Events.

Risk Scores
TIMI GRACE
History
Age
Hypertension
Diabetes
Smoking
↑ Cholesterol
Family history
History of CAD
Age
Presentation
Severe angina
Aspirin within 7 days
Elevated markers
ST-segment deviation
Heart rate
Systolic BP
Elevated creatinine
Heart failure
Cardiac arrest
Elevated markers
ST-segment deviation
Antman EM, et al. JAMA 2000;284:835–42. Eagle KA, et al. JAMA 2004;291:2727–33.
GRACE = Global Registry of Acute Coronary Events; TIMI = Thrombolysis in Myocardial Infarction.

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