2
Antithrombotic Agents
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and ex...
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 Fact...
2. Platelet phase
 Blood vessel wall (endothelial cells) prevent platelet
adhesion & aggregation
 Platelets contain rece...
3. Coagulation Phase
 2 major pathways
 Intrinsic pathway
 Extrinsic pathway
 Both converge at a common point
 Clotti...
Intrinsic
Pathway
 All clotting
factors are
within the blood
vessels
 Clotting: slower
 aPTT
Extrinsic Pathway
 Initia...
Thrombi
Arterial
 Occur in areas of rapid
flow (arteries)
 In response to an injured
or abnormal vessel wall
 White
 C...
4. Fibrinolysis
Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to...
Drug Class Prototype Action Effect
1. Anticoagulant
Heparin Inactivation of clotting
factors
Prevent DVT
Oral Warfarin Dec...
13
Antithrombotic Agents
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and e...
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
P...
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. ...
19
Different mechanisms of antiplatelet drugs
1. COX-1 inhibitors: ASA, Omega 3
2. Phosphodiesterase inhibitors
Dipyridamo...
Adapted from: Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Desai NR, Bhatt DL. JACC Cardiovasc Interv. 2010;3:571-5...
Aspirin: some background
 Patented by Bayer in 1893
 One of the oldest drugs
 One of the most consumed drugs
(Productio...
Pharmacokinetics
 Blocks pain impulses in the CNS
 Peripheral blood vessel dilator
 Fever Reducer
 Decreases platelet ...
23
Aspirin: Mechanism of Action
Membrane Phospholipids
Arachadonic Acid
Prostaglandin H2
COX-1
Thromboxane A2
 Platelet A...
Contraindications ASA
 Trauma (ABSOLUTE)
 Aspirin Allergy (ABSOLUTE)
 GI bleeding (relative, unless actively bleeding)
...
25
Thienopyridine: Mechanism of Action
ADP / ATP
P2Y1
P2X1 P2Y12
Gi2 coupled
Gq coupled
Ca2+ Ca2+ cAMP
Platelet shape chan...
27
Antiplatelet Therapy: Common Oral Agents
Acetylsalicylic acid
(ASA)
Clopidogrel
bisulfate*
Ticlopidine
hydrochloride*
T...
28
Thienopyridines
• Plavix® (Clopidogrel) 75mg daily
• Efient® (Prasugrel) 10mg daily
• Brilinta® (Ticagrelor) 90mg daily...
Cilostazol
Drug Class: Phosphodiesterase III
inhibitor derivative
Approved: January 1999
Dosing: 100 mg bid
Pharmacologic ...
Medications for Patients With PAD
Therapeutic Goal
Drug
To Reduce
Ischemic
Events
To Improve
Claudication
Symptoms
Clopido...
Yusuf S et al. Circulation 2003;107:966-972
CURE: Very Early Efficacy of
Clopidogrel in NSTE ACS
Hours After Randomization...
32
Clopidogrel Evidence: Secondary Prevention
Clopidogrel versus Aspirin in Patients at Risk of Ischemic
Events (CAPRIE) T...
33
Clopidogrel Evidence: Secondary Prevention
Clopidogrel in Unstable Angina to Prevent Recurrent Events
(CURE) Trial
0.00...
Evolution of Antiplatelet Therapy in ACS
Placebo APTC CURE TRITON-TIMI 38
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
High...
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 pla...
Therapy for the Metabolic Syndrome
(NCEP- Adult Treatment Panel III)
 Reducing weight and increasing physical activity
 ...
Recommendations:
Antiplatelet Agents (1)
• Consider aspirin therapy (75–162 mg/day) (C)
– As a primary prevention strategy...
Recommendations:
Antiplatelet Agents (2)
• Aspirin should not be recommended for
CVD prevention for adults with diabetes a...
Recommendations:
Antiplatelet Agents (3)
• Use aspirin therapy (75–162 mg/day)
– Secondary prevention strategy in those wi...
Clinical Assessment
Prehospital emergency medical system (EMS)
providers should administer 162 to 325 mg of
aspirin (chewe...
Antiplatelet Therapy
Aspirin should be administered to UA/NSTEMI
patients as soon as possible after hospital
presentation ...
Antiplatelet Therapy
Patients with definite UA/NSTEMI at medium or high risk and in
whom an initial invasive strategy is s...
Initial Conservative Strategy:
Antiplatelet Therapy
A loading dose of P2Y12 receptor inhibitor therapy is
recommended for ...
Antiplatelet therapy
Aspirin : as soon as possible (165-325 mg)
- (non enteric formulation orally or chewed).
-Continued i...
From: Clopidogrel and Proton Pump Inhibitors: Influence of Pharmacological Interactions on Clinical
Outcomes and Mechanist...
From: Clopidogrel and Proton Pump Inhibitors: Influence of Pharmacological Interactions on Clinical
Outcomes and Mechanist...
From: Clopidogrel and Proton Pump Inhibitors: Influence of Pharmacological Interactions on Clinical
Outcomes and Mechanist...
the FDA recommendation goes far beyond the two drugs studied. Nexium and
Prilosec interfere with Plavix not because they a...
Use of Proton pump inhibitors
Interfere with the metabolism of clopidogrel
-
- Lansoprazole inhibits CYP450 2C19
- Rabepra...
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 wi...
Secondary prevention
(including patients with type 2 diabetes)
(1) Aspirin: use for all patients unless contraindicated
(2...
Antiplatelet Therapy to Support
Primary PCI for STEMI
Reperfusion at a PCI-Capable Hospital
2013 ACCF/AHA Guideline
Antiplatelet Therapy to Support
Primary PCI for STEMI
Aspirin 162 to 325 mg should be given before primary PCI.
After PCI,...
Antiplatelet Therapy to Support
Primary PCI for STEMI
A loading dose of a P2Y12 receptor inhibitor should be given as
earl...
Antiplatelet Therapy to Support
Primary PCI for STEMI
P2Y12 inhibitor therapy should be given for 1 year to patients with
...
Metabolism of P2Y12 Receptor
Antagonists
Adapted from: Schomig A. NEJM. 2009;361(11):1108-1111.
Effient (Prasugrel) Produc...
Properties of P2Y12 Receptor
Antagonists
Clopidogrel Prasugrel Ticagrelor
Requires Metabolic
Activation through
CYP2C19
Ye...
Antiplatelet Therapy to Support
Primary PCI for STEMI
It is reasonable to use 81 mg of aspirin per day in preference to
hi...
Antiplatelet Therapy to Support
Primary PCI for STEMI
It is reasonable to start treatment with an intravenous GP IIb/IIIa
...
Antiplatelet Therapy to Support
Primary PCI for STEMI
It may be reasonable to administer intravenous GP IIb/IIIa
receptor ...
Antiplatelet Therapy to Support
Primary PCI for STEMI
Prasugrel should not be administered to patients with a history of
p...
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 co...
Antiplatelet Agents
GP IIb/IIIa Inhibitors (cont.)
 Monoclonal antibody: abciximab
 Natural products — disintegrin famil...
Antiplatelet Agents
GP IIb/IIIa Inhibitors (cont.)
 Abciximab, eptifibatide, tirofiban: 35,000
patients studied in ACS an...
Initial Conservative Strategy:
Antiplatelet Therapy
For UA/NSTEMI patients in whom an initial
conservative strategy is sel...
Initial Conservative Strategy:
Antiplatelet Therapy
The use of upstream GP IIb/IIIa inhibitors
may be considered in high-r...
Initial Conservative Strategy:
Antiplatelet Therapy
Abciximab should not be administered to
patients in whom PCI is not pl...
• Vorapaxar:
 First-in-class
 Oral PAR-1
inhibitor
• Metabolism:
 Primarily hepatic
via CYP 3A4
 Terminal half-life:
~...
Target Platelet Receptor
TxA2
Terutroban
vWF
Gp1b ARC1779
ALX-0081
AJW200
Thrombin
PAR-1
Vorapaxar
SCH 205831
Atopaxar
ADP...
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 Progr...
Antithrombotic agents: summary
• Antiplatelet agents: Aspirin . This well tested, widely used, and cheap agent
• Ticlopidi...
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and extension
Thrombolytic age...
Anticoagulants – historical development
1916 1924 1936 1940 1950s 20061970s 1976 1980s 1990s 2001
Oral
Injection
Spoiled
s...
Enhances
Antithrombin Activity
Enhances
Antithrombin Activity
Warfarin
Enhances
Antithrombin Activity
Dabigatran
Oral Anticoagulant Target Sites
Antithrombin
Fibrinogen
Factor II
(Prothrombin)
Fibrin
Factor IIa
(Thrombin)
Factor X
Fact...
85
Current Options
Vitamin K Antagonist
Unfractionated Heparin
(UFH)
Low Molecular Weight
Heparin (LMWH)
Direct Thrombin
I...
Initial Invasive Strategy:
Anticoagulant Therapy
Anticoagulant therapy should be added to
antiplatelet therapy in UA/NSTEM...
Organization to
Assess Strategies for Ischaemic
Syndromes (OASIS-5)
•Fondaparinux (fonda) (2.5 mg/day, n=10,057) vs enox (...
OASIS 5 Cumulative Risk of Death, MI, or
Refractory Ischemia
*p for noninferiority; †p for superiority. Yusuf S, et al. N ...
89
90
91
92
93
Bleeding Risk Assessment Tools
1.ACS – CRUSADE
2. AF – HAS – BLED
3.DVT/PE – Out Patient Bleeding Risk Index
4.DVT- PE ...
94
Dosage Strength Tablet Color
1mg Pink
2mg Lavender
2.5mg Green
3mg Tan
4mg Blue
5mg Peach
6mg Teal
7.5mg Yellow
10mg Wh...
CRUSADE Bleeding Score Nomogram
Note: Heart rate is truncated @ <70 bpm;
CrCl: Cockcroft-Gault is truncated @ >90 mL/min; ...
Risk Quintiles
 Patients were categorized into quintiles of risk
groups based on their CRUSADE Bleeding
Score
Risk N Min ...
99
Outpatient Bleeding Risk Index
100
Bleeding Risk Assessment Score for Outpatients on Warfarin
The HAS-BLED Score
101
102
HEMORR2HAGES
103
Indications of Anticoagulant Therapy
• Treatment & Prevention of Deep Venous Thrombosis
• Pulmonary Emboli
• Prevention of...
YING - YANG PRINCIPLE
• With every approach to reduce thrombosis,
however, there is an accompanying risk of
increasing ble...
Thrombosis vs Bleeding
• They both increase morbidity and mortality
• Balancing both ends of the spectrum is
essential, an...
Atrial Fibrillation Update 2012
1. Rate control vs. Rhythm control
2. Who requires anticoagulants and
which ones?
3. What ...
Simplified classification
• Paroxysmal→spontaneously terminate <7 days
• Persistent→lasts >7 days and requires
interventio...
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?
MAI...
www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429
The management cascade for patients with AF
ACEI =...
www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429
Risk factor-based point-based scoring
system - CHA...
www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429
Use of oral anticoagulation for
stroke prevention ...
www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429
Approach to thromboprophylaxis in AF
AF = atrial f...
Copyright © The American College of Cardiology.
All rights reserved.
From: Practical Management of Anticoagulation in Pati...
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
4...
AT: antithrombin
Fondaparinux: xa
TL: Weitz JI et al. New Antithrombotic Drugs: antithrombotic therapy and prevention of
t...
New Anticoagulants
TFPI (tifacogin)
Fondaparinux
Idraparinux
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
Betrixaban
TAK 44...
Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban
Mechanism
of action
Thrombin
inhibitor
Factor Xa
inhibitor
Factor...
March 2011
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Dab...
1) Documented atrial fibrillation and
2) One additional risk factor for stroke:
a) History of previous stroke, TIA, or sys...
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
<0.00...
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...
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
Dabigat...
RELY
• Dabigatran 110 mg twice daily
– Equal to warfarin in stroke prevention
• Warfarin 1.69%/yr – dabigatran (110mg) 1.5...
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
P-value
110 vs. W
P-value
150 vs. W
Number of patients (n) 6015 6076 6022
Maj...
Less
Bleeding
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Warfarin
1.5 2.0 2.5 3.0...
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment Stroke Risk
(/year)
No Thera...
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment Stroke Risk
(/year)
No Thera...
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment Stroke Risk
(/year)
No Thera...
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment Stroke Risk
(/year)
No Thera...
Stroke Prevention in Atrial Fibrillation
-The Natural History of Atrial Fibrillation
Cardiovascular Outcomes
(Stroke, Deat...
Stroke Prevention in Atrial Fibrillation
-The Natural History of Atrial Fibrillation
Cardiovascular Outcomes
(Stroke, Deat...
Dabigatran vs. Warfarin
Noninferiority trial randomly assigned 18,113 patients who had atrial fibrillation and a risk of s...
2012 ACCP Guidelines for Antithrombotic Therapy
in Patients Undergoing Cardioversion for AF
Patient features Recommended a...
(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 pre...
Initial Conservative Strategy:
Anticoagulant Therapy
Anticoagulant therapy should be added to
antiplatelet therapy in UA/N...
Initial Conservative Strategy:
Anticoagulant Therapy
For UA/NSTEMI patients in whom an initial
conservative strategy is se...
149
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and extension
Thrombolytic...
PathophysiologyStable Angina
•Progressive
narrowing of coronary
lumen
•Stable fibrous cap
Unstable Angina
•Progressive
nar...
Clinical manifestations of arterial
thrombosis
UA/NQMI:
Partially-occlusive thrombus
(primarily platelets)
Intra-plaque
th...
Primary PCI
Common thrombolytics regimens for
STEMI1
Initial treatment Co-therapy Contraindications
Streptokinase (SK) 1.5 million U i...
OASIS-5: PCI Substudy
• ACS pts with cath or PCI during hospitalization (n=20,078)
• Fondaparinux vs enoxaparin (if PCI <6...
Initial Conservative Strategy:
Additional Management Considerations
For UA/NSTEMI patients in whom a conservative
strategy...
171
Thrombolytic Therapy
• -Thrombolytic therapy (urokinase, strepto-
kinase, alteplase, anistreplase, reteplase)
also may...
172
Antiplatelet drugs: interfere
with platelet activity
Anticoagulants: prevent clot
formation and extension
Thrombolytic...
•Age ≥ 65 years
•At least 3 risk factors for CAD
•Prior coronary stenosis of ≥ 50%
•ST-segment deviation on ECG presentati...
TIMI
Risk
Score
All-Cause Mortality, New or Recurrent MI, or Severe
Recurrent Ischemia Requiring Urgent Revascularization
...
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 ...
Risk Scores
TIMI GRACE
History
Age
Hypertension
Diabetes
Smoking
↑ Cholesterol
Family history
History of CAD
Age
Presentat...
Antithrombin therapy
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  • vascular permeability factor, VPF : yếu tố tính thấm mạch máu
  • aPPT viết tắt Activated Partial Thromboplastin Time ; PT : Prothrombin TimeTCK Cephalin – kaolin – time ; TQ : Quick Time
  • Deep Vein Thrombosis
  • ADENOSINE DIPHOSPHATE
  • Here are some other, newer thienopyridines. They are more expensive and so their indication is restricted to patients after MI undergoing Percutaneous coronary intervention, as an alternative to Plavix.
  • In 2010, a position statement of the ADA, AHA, and the American College of Cardiology Foundation (ACCF) updated prior joint recommendations for primary prevention1Recommendations for the use of antiplatelet agents2 are summarized in three slidesSlide 1 of 3Low-dose (75–162 mg/day) aspirin use for primary prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk (10-year risk of CVD events &gt;10%) and who are not at increased risk for bleedingThis generally includes most men over age 50 years and women over age 60 years who also have one or more of the following major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, or albuminuria
  • However, aspirin is no longer recommended for those at low CVD risk (women under age 60 years and men under age 50 years with no major CVD risk factors; 10-year CVD risk &lt;5%), as the low benefit is likely to be outweighed by the risks of significant bleedingClinical judgment should be used for those at intermediate risk (younger patients with one or more risk factors, or older patients with no risk factors; those with 10-year CVD risk of 5–10%) until further research is available. Use of aspirin in patients under the age of 21 years is contraindicated due to the associated risk of Reye’s syndromeRecommendations for the use of antiplatelet agents are summarized in three slidesSlide 2 of 3Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk &lt;5%, such as in men &lt;50 and women &lt;60 years of age with no major additional CVD risk factors), since the potential adverse effects from bleeding likely offset the potential benefits (C)In patients in these age groups with multiple other risk factors (e.g., 10-year risk 5%-10%) clinical judgment is required (E)
  • Recommendations for the use of antiplatelet agents1 are summarized in three slidesSlide 3 of 3Use aspirin therapy (75-162 mg/day) as a 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) is reasonable for up to a year after an acute coronary syndrome (B)Clopidogrel has been demonstrated to reduce CVD events in diabetic individuals2 It is recommended as adjunctive therapy in the first year after an acute coronary syndrome or as alternative therapy in aspirin-intolerant patients
  • LEVEL OF EVIDENCE
  • LEVEL OF EVIDENCE
  • LEVEL OF EVIDENCE
  • Their indication is restricted to the peri-Percutaneous coronary intervention period, and they are used in combination with aspirine and plavix to achieve a higher grade of platelet inactivation. Obviously, the bleeding risk in these patients is extremely high.
  • I have simplified graphic and content. I don&apos;t think we need P2Y 1 receptor. I would also leave out PAR-4.
  • For the subgroup analysis, patients were divided into approximately equal sized quintiles of risk groups based on their CRUSADE Bleeding Score
  • For ease of ease of use and convenience we developed a website Here is an example of the user interface. After entering in the appropriate range of values for each predictor, this online calculator will immediatiely provide an output of the CRUSADE Bleeding Score and the corresponding Risk of in-hospital major bleeding.
  • Patients with paroxysmal AF can be highly symptomaticThree main aims of treatment for paroxysmal AF are to: suppress paroxysms of AF and maintain sinus rhythm control heart rate during paroxysms of AF prevent complications Treatment strategies include out-of-hospital initiation of antiarrhythmic drugs: ‘pill in the pocket’ approachPatients with paroxysmal AF carry the same risks of stroke and thromboembolism as those with persistent AF
  • Antithrombin therapy

    1. 1. 2 Antithrombotic Agents Antiplatelet drugs: interfere with platelet activity Anticoagulants: prevent clot formation and extension Thrombolytic agents: dissolve existing thrombi
    2. 2. 1. Vascular Phase 2. Platelet Phase 3. Coagulation Phase 4. Fibrinolytic Phase
    3. 3. 1. Vascular Phase  Vascular Conductance  Exposure to tissues activate tissue factor and initiate coagulation Tissue Factor
    4. 4. 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
    5. 5. 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
    6. 6. 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
    7. 7. 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.
    8. 8. 4. Fibrinolysis Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks down fibrin clots
    9. 9. 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
    10. 10. 13 Antithrombotic Agents Antiplatelet drugs: interfere with platelet activity Anticoagulants: prevent clot formation and extension Thrombolytic agents: dissolve existing thrombi
    11. 11. Plaque Fissure or Rupture Platelet Aggregation Platelet Activation Platelet Adhesion Thrombotic Occlusion
    12. 12. 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
    13. 13. Prevention of bleeding just as important as prevention of ischemia: Safety Efficacy
    14. 14. 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
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. 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.
    19. 19. 23 Aspirin: Mechanism of Action Membrane Phospholipids Arachadonic Acid Prostaglandin H2 COX-1 Thromboxane A2  Platelet Aggregation Vasoconstriction Prostacyclin  Platelet Aggregation Vasodilation Aspirin
    20. 20. 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
    21. 21. 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
    22. 22. 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
    23. 23. 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)
    24. 24. 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
    25. 25. Medications for Patients With PAD Therapeutic Goal Drug To Reduce Ischemic Events To Improve Claudication Symptoms Clopidogrel Yes No (Plavix® ) Cilostazol No Yes (Pletal® )
    26. 26. 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
    27. 27. 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
    28. 28. 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
    29. 29. 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.
    30. 30. Adjunctive Antithrombotic Therapy to Support Reperfusion With Fibrinolytic Therapy
    31. 31. Adjunctive Antithrombotic Therapy to Support PCI After Fibrinolytic Therapy
    32. 32. 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)
    33. 33. Therapy for the Metabolic Syndrome (NCEP- Adult Treatment Panel III)  Reducing weight and increasing physical activity  Lowering Triglycerides, raising HDL-c  Treating hypertension  Aspirin
    34. 34. 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.
    35. 35. Recommendations: Antiplatelet Agents (2) • 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) ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32.
    36. 36. Recommendations: Antiplatelet Agents (3) • 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) ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32.
    37. 37. 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
    38. 38. 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Modified 2012 III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Modified 2012 See recommendation for LOE
    39. 39. Antiplatelet Therapy 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) III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Modified 2012 See recommendation for LOE
    40. 40. Initial Conservative Strategy: Antiplatelet Therapy 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) III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Modified 2012 See recommendation for LOE
    41. 41. 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
    42. 42. 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.
    43. 43. 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 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.
    44. 44. 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 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.
    45. 45. 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)
    46. 46. 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
    47. 47. Asperin, please. Doctor Take an asperin every day, but before you swallow it, take it out for a five-mile walk
    48. 48. 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
    49. 49. 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
    50. 50. Antiplatelet Therapy to Support Primary PCI for STEMI Reperfusion at a PCI-Capable Hospital 2013 ACCF/AHA Guideline
    51. 51. Antiplatelet Therapy to Support Primary PCI for STEMI 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
    52. 52. Antiplatelet Therapy to Support Primary PCI for STEMI 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
    53. 53. Antiplatelet Therapy to Support Primary PCI for STEMI 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.
    54. 54. 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.
    55. 55. 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.
    56. 56. Antiplatelet Therapy to Support Primary PCI for STEMI It is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses after primary PCI. I IIa IIb III
    57. 57. Antiplatelet Therapy to Support Primary PCI for STEMI 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
    58. 58. Antiplatelet Therapy to Support Primary PCI for STEMI 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
    59. 59. Antiplatelet Therapy to Support Primary PCI for STEMI Prasugrel should not be administered to patients with a history of prior stroke or transient ischemic attack. I IIa IIb III Harm
    60. 60. Antiplatelet Agents GP IIb/IIIa Inhibitors Fibrinogen GP IIb/IIIa Receptor GP IIb/IIIa Inhibitors
    61. 61. 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
    62. 62. 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
    63. 63. 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
    64. 64. Initial Conservative Strategy: Antiplatelet Therapy 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
    65. 65. Initial Conservative Strategy: Antiplatelet Therapy 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII Modified 2012
    66. 66. Initial Conservative Strategy: Antiplatelet Therapy 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII No Benefit Modified 2012 III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
    67. 67. • 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
    68. 68. 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
    69. 69. New Target for Antiplatelet Therapy: Thrombin Receptor Antagonist (TRA) Thrombin Xa+Va+II Thrombus Fibrinogen Fibrin TRA X
    70. 70. 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
    71. 71. 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
    72. 72. Antiplatelet drugs: interfere with platelet activity Anticoagulants: prevent clot formation and extension Thrombolytic agents: dissolve existing thrombi
    73. 73. 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
    74. 74. Enhances Antithrombin Activity
    75. 75. Enhances Antithrombin Activity Warfarin
    76. 76. Enhances Antithrombin Activity Dabigatran
    77. 77. 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
    78. 78. 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
    79. 79. 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
    80. 80. 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.
    81. 81. 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†
    82. 82. 89
    83. 83. 90
    84. 84. 91
    85. 85. 92
    86. 86. 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
    87. 87. 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
    88. 88. 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
    89. 89. 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%
    90. 90. 99 Outpatient Bleeding Risk Index
    91. 91. 100 Bleeding Risk Assessment Score for Outpatients on Warfarin The HAS-BLED Score
    92. 92. 101
    93. 93. 102 HEMORR2HAGES
    94. 94. 103
    95. 95. 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.
    96. 96. 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.
    97. 97. 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.
    98. 98. 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?
    99. 99. 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
    100. 100. Goals of Therapy 1. Relieve symptoms 2. Prevent Stroke 3. Prevent Heart Failure
    101. 101. 1.5% in < 60 yrs 23.5% in > 80 yrs
    102. 102. 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
    103. 103. 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.
    104. 104. www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429 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.
    105. 105. www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429 Use of oral anticoagulation for stroke prevention in AF AF = atrial fibrillation; OAC = oral anticoagulant; TIA = transient ischaemic attack.
    106. 106. www.escardio.org/guidelines European Heart Journal (2010) 31, 2369-2429 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).
    107. 107. 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.
    108. 108. 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
    109. 109. AT: antithrombin Fondaparinux: xa TL: Weitz JI et al. New Antithrombotic Drugs: antithrombotic therapy and prevention of thrombosis. Chest 2012; 141: ed 120s- e151s.
    110. 110. 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
    111. 111. 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
    112. 112. March 2011
    113. 113. 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. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Study Design
    114. 114. 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 Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Inclusion Criteria • N Engl J Med 2009; 361 : 1139-51.
    115. 115. 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. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Primary Outcome: Stroke or Systemic Embolism
    116. 116. 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 Dabigatran etexilate 150 mg RRR 34% Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Primary Outcome: Stroke or Systemic Embolism • N Engl J Med 2009; 361: 1139-51.
    117. 117. 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 Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 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. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Intracranial Bleeding
    118. 118. 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
    119. 119. 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 Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Major Bleeding in the RE-LY Study • N Engl J Med 2009; 361: 1139-51.
    120. 120. Less Bleeding Stroke Prevention in Atrial Fibrillation -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
    121. 121. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 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
    122. 122. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 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 64%
    123. 123. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 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 34%
    124. 124. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 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 76%
    125. 125. Stroke Prevention in Atrial Fibrillation -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
    126. 126. Stroke Prevention in Atrial Fibrillation -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
    127. 127. 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 3.36% per year in the warfarin group 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 0.38% per year in the warfarin group 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 4.13% per year in the warfarin group 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
    128. 128. 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
    129. 129. (EuropeanMedicinesAgency.Pradaxa.SummaryofProductCharacteristics. htttp://www.ema.europa.eu/docs/en_GB/document_library)
    130. 130. 144 Stroke PreventionStroke Prevention Adverse Events Starting dose 110 vs 150 mg bid ?
    131. 131. 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
    132. 132. Initial Conservative 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 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII *Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.
    133. 133. Initial Conservative Strategy: Anticoagulant Therapy 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII *Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.
    134. 134. 149 Antiplatelet drugs: interfere with platelet activity Anticoagulants: prevent clot formation and extension Thrombolytic agents: dissolve existing thrombi
    135. 135. 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
    136. 136. 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.
    137. 137. Primary PCI
    138. 138. 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 40 mg if 70 kg to <80 kg 45 mg if 80 kg to <90 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
    139. 139. 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
    140. 140. Initial Conservative Strategy: 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. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII See a-d for LOE Modified 2012 Modified 2012
    141. 141. 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).
    142. 142. 172 Antiplatelet drugs: interfere with platelet activity Anticoagulants: prevent clot formation and extension Thrombolytic agents: dissolve existing thrombi
    143. 143. •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.
    144. 144. 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.
    145. 145. 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.
    146. 146. 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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