1. Role of Anticoagulants in ACS
Bashir Hanif, MD, FACC, FSCAI
Medical Director
Chief of Cardiology
Tabba Heart Institute

2. Overview Brief Epidemiology and Pathophysiology
Overview of Anticoagulants used in ACS
Is there Evidence
What the Guidelines say?
Innovative Ideas from South Korea

4. Epidemiology of ACS in the United States
Single largest cause of death
515,204 US deaths in 2000
1 in every 5 US deaths
Incidence
1,100,000 Americans will have a new or recurrent coronary attack each year and about 45% will die*
550,000 new cases of angina per year
Prevalence
12,900,000 with a history of MI, angina, or both
Acute coronary syndromes are the leading cause of death in the U.S., accounting for over 500,000 deaths each year and one in every five deaths.
* Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. ACS indicates acute coronary syndrome; MI, myocardial infarction; ARIC, Atherosclerotic Risk in Communities; and CHD, coronary heart disease. From American Heart Association. Heart Disease and Stroke Statistics—2003 Update.

5. Emergency Department Visits Annually in the United States

6. Hospitalizations in the U.S. Due to ACS
Acute Coronary Syndromes*
1.57 Million Hospital Admissions - ACS
UA/NSTEMI†
STEMI
1.24 million Admissions per year
0.33 million Admissions per year
*Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.
Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.

7. Acute Coronary Syndrome
NSTEMI
Presentation
Working Dx
ECG
Cardiac
Biomarker
Final Dx
NQMI
Qw MI UA
Unstable
Angina
Ischemic Discomfort
Acute Coronary Syndrome
Myocardial Infarction
ST Elevation
No ST Elevation
Non-ST ACS
Libby P. Circulation 2001;104:365, Hamm CW, Bertrand M, Braunwald E, Lancet 2001; 358: ; Davies MJ. Heart 2000; 83:
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 1. Reprinted with permission.

8. Acute Coronary Syndromes (ACS)
SUDDEN DEATH
Unstable Angina
Coronary Arterial Thrombosis
Because all acute coronary syndromes share a common pathophysiology, one acute coronary syndrome can progress to the other. A proportion of patients with unstable angina will progress to non-ST-segment elevation MI and some patients with non-ST-segment elevation MI will progress on to develop complete occlusion and ST-segment elevation MI. Some patients will progress to sudden death.
Non-ST-Elevation Myocardial Infarction
ST-Elevation Myocardial Infarction
SUDDEN DEATH
Van de Werf F. Throm Haemost. 1997; 78(1):

9. Causes of UA/NSTEMI*
Thrombus or thromboembolism, usually arising on disrupted or eroded plaque
Occlusive thrombus, usually with collateral vessels†
Subtotally occlusive thrombus on pre-existing plaque
Distal microvascular thromboembolism from plaque-associated thrombus
Thromboembolism from plaque erosion
Non–plaque-associated coronary thromboembolism
Dynamic obstruction (coronary spasm‡ or vascoconstriction) of epicardial and/or microvascular vessels
Progressive mechanical obstruction to coronary flow
Coronary arterial inflammation
Secondary UA
Coronary artery dissection§
*These causes are not mutually exclusive; some patients have 2 or more causes. †DeWood MA, et al. N Engl J Med 1986;315:417–23. ‡May occur on top of an atherosclerotic plaque, producing missed-etiology angina or UA/NSTEMI. §Rare. Modified with permission from Braunwald E. Circulation 1998;98:2219–22. Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Table 3.

10. Pathogenesis of ACS Plaque rupture Platelet adhesion
Platelet activation
Partially occlusive arterial thrombosis & unstable angina
Acute coronary syndromes occur as a result of thrombus formation in response to rupture of an atherosclerotic plaque in the vessel wall. Spontaneous or intervention-induced plaque rupture promotes adhesion of platelets from the circulation, followed by platelet activation and platelet aggregation. Platelet aggregation leads to the formation of partially occlusive coronary thrombi, which clinically manifest as unstable angina (with occlusions > 70%), or, if prolonged occlusion results in myocardial damage, as NSTEMI. NSTEMI is caused by dislodgement and embolization of platelet-rich microthrombi into the coronary microvasculature, blocking blood flow, and causing heart muscle death. Complete occlusion of coronary arteries (>90%) manifests clinically as STEMI.
Microembolization & non-ST-segment elevation MI
Totally occlusive arterial thrombosis & ST-segment elevation MI
White HD. Am J Cardiol 1997;80 (4A):2B-10B.

11. The Role of Platelets in Atherothrombosis

12. Thrombus Formation and ACSUA
NQMI
STE-MI
Plaque Disruption/Fissure/Erosion
Thrombus Formation
Non-ST-Segment Elevation Acute Coronary Syndrome (ACS)
ST-Segment Elevation (ACS)
Old
Terminology:
New
It is now recognized that unstable angina (UA), non-Q-wave myocardial infarction (NQMI), and ST-segment elevation myocardial infarction (STE-MI) are all parts of the spectrum of clinical manifestations of acute coronary syndrome (ACS). The older terminology has now been replaced with terminology that divides ACS into non-ST-elevation ACS (NSTE-ACS) and ST-segment-elevation. All the slides in this teaching set deal with NSTE-ACS.

13. Mechanical Vasoconstrictive Plaque Rupture Thrombus
Distal Embolization
Serotonin Release
Mechanical Plugging
Vasoconstriction

14. Structure of Thrombus Following Plaque Disruption
UA/NSTEMI: Partially-occlusive thrombus (primarily platelets)
Intra-plaque thrombus (platelet-dominated)
Plaque core
STEMI: Occlusive thrombus (platelets, red blood cells, and fibrin)
Intra-plaque thrombus (platelet-dominated)
SUDDEN DEATH
The clinical manifestation of coronary thrombosis depends on the extent and duration of thrombotic occlusion. Unstable angina and non-ST-segment elevation MI are characterized by mural, platelet-rich thrombi, which do not completely block coronary blood flow and therefore cause ischemia of relatively short duration.
The aggregated platelets can serve as a substrate for further thrombus propagation, leading to formation of an occlusive red thrombus formed by entrapment of red blood cells within the fibrin mesh. This complete occlusion results in abrupt and persistent ischemia that clinically manifests as ST-segment elevation MI. Left untreated, occlusion of the coronary arteries can lead to sudden cardiac death.
UA = Unstable Angina
NSTEMI = Non-ST-segment Elevation Myocardial Infarction
STEMI = ST-segment Elevation Myocardial Infarction
White HD. Am J Cardiol 1997;80 (4A):2B-10B.

15. The Role of the Platelet in Non-ST-segment Elevation Acute Coronary Syndromes
(NSTE ACS)
Results from cross-linking of platelets by fibrinogen at platelet receptors GP IIb-IIIa at site of plaque rupture
Generally caused by partially-occlusive, platelet-rich thrombus in a coronary artery
Unobstructed lumen
GP IIb-IIIa
Platelet
In patients with NSTE ACS, chest pain is usually caused by prolonged partial occlusion of coronary arteries by platelet-rich thrombi, as shown in the photograph on the left side. Platelet-rich thrombi that precipitate NSTE ACS are formed by platelet aggregation, which involves binding of a single molecule of fibrinogen to two GP IIb-IIIa receptors on adjacent platelets. For this reason, disaggregation of existing thrombi1, as well as prevention of platelet aggregation and formation of platelet-rich thrombi with inhibitors of the platelet receptor GP IIb-IIIa is a rational strategy for treatment of patients with NSTE ACS.
____________________________________________________________________
1Moser M, et al. J Cardiovasc Pharmacol 2003;41:
Thrombus
Fibrinogen
Ruptured plaque
Artery wall
Van de Werf F. Throm Haemost 1997;78(1):

16. The Role of the Thrombus in ST-segment Elevation MI (STEMI)
Generally caused by a completely occlusive thrombus in a coronary artery
Results from stabilization by fibrin mesh of a platelet aggregate at site of plaque rupture
The photograph on the left side shows complete thrombotic occlusion of a coronary artery, which manifests clinically as a STEMI. The completely occlusive thrombus consists of a platelet-rich core (formed by platelet aggregation) and superimposed network/mesh of cross-linked fibrin molecules (formed by activity of the coagulation cascade) and entrapped red blood cells, as shown in the graphic on the right side.
This picture of a clot shows a fibrin mesh, formed by bonds between activated platelets and fibrinogen. Trapped inside are red blood cells. In STEMI patients, approximately >90% of the culprit vessel is occluded by thrombus.
platelet
RBC
fibrin mesh
Van de Werf F. Throm Haemost 1997;78(1):

18. Antiplatelet and Anticoagulant Agents in the Setting of NSTE ACS

21. Another Innovative Idea Nice way of Buttering!!!

23. Anticoagulants Heparins Factor X-A Inhibitor
Unfractionated heparin (UFH)
Low molecular weight heparin (LMWH)
Enoxaparin, Dalteparin
Factor X-A Inhibitor
Fondaparinux
Direct Thrombin Inhibitors
Bivalirudin: reversible binding
Lepirudin: irreversible binding
Argatroban: reversible binding
Hirudin

24. Anticoagulants and Gymnastics
Anticoagulation is like a
performance beam
Both efficacy and safety are
important.
If you fail to balance efficacy
and safety patient may get hurt

25. The Search for an Anticoagulant That Balances Safety and Efficacy
Optimal Safety and Efficacy
Thrombosis
Bleeding
Dose (concentration) of Anticoagulant

26. Unfractionated Heparin
An unbranched heteropolysaccharide Chain

27. Unfractionated Heparin (UFH)
Binds antithrombin & inhibits clotting factors Xa & IIa (thrombin)
IV bolus followed by infusion, adjust according to aPTT or antifactor Xa levels
Can be used in patients with renal dysfunction

30. Unfractionated Heparin (UFH)
NSTE ACS
preferred anticoagulant following angiography in patients undergoing CABG (Class 1)
option for patients undergoing planned early angiography & revascularization (Class 1)
may be used in patients in whom an initial conservative strategy is planned (Class 1)
1st line anticoagulant for STE ACS & PCI
administered with a fibrin selective fibrinolytic (Class 1)

31. Unfractionated Heparin (UFH)
Contraindications:
history of heparin induced thrombocytopenia (HIT)
active bleeding
severe bleeding risk
recent stroke
Adverse effects:
bleeding
HIT

33. Enoxaparin Contraindications:
Shorter chain length compared to UFH
more predictable effects
Binds antithrombin, inhibits factors Xa & IIa
Contraindications:
active bleeding, severe bleeding risk
history of HIT
recent stroke
CrCl < 15 ml/min
avoid in CABG patients
Dose: 1 mg/kg every 12 hrs (renal adjustment required)
Adverse effects: bleeding & HIT (lesser extent than UFH)

34. Enoxaparin STEMI NSTEMI ACS
not studied in primary PCI (Class 2b as alternative to UFH)
NSTEMI ACS
option for patients undergoing planned early angiography and revascularization (Class 2a)
UFH recommended over enoxaparin or fondaparinux (Class 1b)
may be used in patients in whom an initial conservative strategy is planned (Class 1)
fondaparinux recommended over enoxaparin (Class 1a)
enoxaparin recommended over UFH (Class 1b)
Schünemann HJ, Hirsh J, Guyatt G, et al. Executive Summary: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines (8th Edition). Chest. 2008;133;

35. Comparison of LMWHs & UFH

36. Limitations with Current Anticoagulation Therapy
Agent
Disadvantages
Heparin
Parenteral administration
Risk of heparin-induced thrombocytopenia (HIT)
Narrow therapeutic window (low bioavailability, short half-life)
Warfarin
Requires frequent monitoring due to:
Narrow therapeutic window
Unpredictable pharmacology
Multiple drug–drug and food–drug interactions
Increased risk of major and minor bleeds
LMWH
Indirect Xa Inhibitor (e.g. fondaparinux)
Long half-life
Limitations related to special patient populations
Direct Thrombin Inhibitors
Current applications limited to cardiovascular management
Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.

37. Innovative Idea To overcome limitations!!!

38. The Evidence

40. Comparison of Heparin + ASA vs ASA Alone
Theroux
RISC
Cohen 1990
ATACS
Holdright
Gurfinkel
Summary Relative Risk
0.67 ( )
Individual studies and cumulative data strongly suggest the additional benefit of risk reduction in patients with unstable angina when unfractionated heparin is added to treatment with aspirin.
0.1 1 10
Heparin + ASA 55/698=7.9%
RR:
Death/MI
ASA Alone 68/655=10.4%
ASA indicates acetylsalicylic acid; RISC, Research on InStability in Coronary artery disease; ATACS, Antithrombotic Therapy in Acute Company Syndromes; RR, relative risk; and MI, myocardial infarction.
Data from Oler A, Whooley MA, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at:

41. ESSENCE: Study Design (n=1607) (n=1564) Enoxaparin 1mg/kg q 12 H
Subcutaneous
+ ASA
Follow-up Visit
Day 14
Follow-up Call
Day 30
Unstable Angina
Non-Q-Wave MI
UFH
IV dose-adjusted
+ ASA
Follow-up Visit
Day 14
Follow-up Call
Day 30
The study design was relatively simple. Half the patients received enoxaparin as a subcutaneous injection 1 mg/kg twice daily in addition to aspirin. Each milligram of enoxaparin contains 100 anti-Xa units. Patients in the second treatment group received standard unfractionated heparin as a continuous intravenous infusion adjusted according to the aPTT nomograms at the individual institutions. The minimum treatment duration was 48 hours, the maximum treatment duration was 8 days. Patients returned for clinical evaluation and ECG at 14 days. A follow-up telephone contact at 30 days assessed additional clinical endpoints and adverse events.
(n=1564)
Treatment Phase
min 48 H, max 8 Days
Follow-up Phase
Cohen, et al. NEJM 1997;337:447-52 21

42. ESSENCE All Randomized30
Heparin
Enoxaparin
23.3% 25
19.8% 20
19.8%
% Death, MI or RA
16.6% 15
RRR 15 % P=0.016
RRR 16.2 % P=0.019
The Kaplan-Meier curves showing time-to-first event are similar. 10 5
Time (Days)
Cohen, et al. NEJM 1997;337:447-52

43. ESSENCE 1 Year Data % Incidence of Triple Endpoint (n= 1564) (n=1607)
Goodman SG, et al. JACC 2000;36:693-8

44. TIMI 11 B Study Design (n=1953) (n=1957) Enoxaparin 30 mg IV bolus +
1mg/kg SC q 12 hr
Fixed Dose
< 65 kg > 65 kg
40 mg mg
q 12 hr SC
(n=1953)
Unstable Angina
Non-Q Wave MI
 24 h
ASA
UFH
70 U/kg IV bolus +
15 U/kg/hr IV  72h
Fixed Dose
Placebo q 12 hr SC
(n=1957)
Acute Phase
min 72H, max 8 Days
Chronic Phase
43 days
Antman et al, Circulation 1999;100:

45. TIMI 11B: Enoxaparin vs. Heparin in NSTE-ACS20
Unfractionated Heparin 1 6 . 7 %
Enoxaparin (Lovenox) 16 12 1 4 . 2 %
Urgent Revascularization
Death, MI or 8
p = 0.03
In TIMI 11B, patients with NSTE-ACS were randomized to treatment with either the low-molecular-weight heparin enoxaparin (30 mg IV then 1 mg/kg SC q 12 hrs) or unfractionated heparin. At 14 days, the composite primary ischemic endpoint was statistically significantly lower in those treated with enoxaparin, similar to what was observed in the ESSENCE study. 4
Relative Risk Reduction = 15% 2 4 6 8 10 12 14
Days
Adapted from Antman EM, et al. Circulation. 1999;100:

46. TIMI 11B-ESSENCE Meta-Analysis Death/MI
Day N
UFH (%)
Enox (%) OR % p
OVERALL
ESSENCE
TIMI 11B 8
0.77 ( ) 23
0.02
7081
3910
3171 B
5.3
4.1
OVERALL
ESSENCE
TIMI 11B 14
0.79 ( ) 21
0.02
7081
3910
3171 B
6.5
5.2
OVERALL
ESSENCE
TIMI 11B 43
0.82 ( ) 18
0.02
7081
3910
3171 B
8.6
7.1
0.5
0.6
0.7
0.8
0.9 1 2
Enox Better
Odds Ratio
UFH Better
T11B ESC 98 17

49. Enoxaparin
ExTRACT trial (Enoxaparin versus Unfractionated Heparin with Fibrinolysis for ST-Elevation MI); n=20,506
enoxaparin 30 mg IV bolus, 1 mg/kg SQ 15 min later then every 12 hr (dose ↓ for age > 75 yr, renal dysfunction)
UFH 60 units/kg IV bolus (maximum: 4000 units) followed by 12 units/kg/hr infusion with adjustments to maintain aPPT 1.5 to 2.0 times the control value
17% risk reduction for death or nonfatal MI in patients on enoxaparin compared to UFH
Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation
myocardial infarction. N Engl J Med 2006;354:1477–1488.

50. Enoxaparin in STEMI: ExTRACT-TIMI 25
STEMI < 6 hours lytic eligible
Acetylsalicylic acid (ASA)
Lytic choice by physician (TNK,TPA, rPA, SK)
Double-blind double dummy phase
Enoxaparin < 75 y: 30 mg IV bolus sc 1.0 mg/kg q 12h (Hosp DC) ≥ 75 y: No bolus sc 0.75 mg/kg q 12h (Hosp DC)
CrCl ≤ 30: 1.0 mg/kg q 24 h
UFH bolus 60 U/kg infusion 12 U/kg/h for ≥ 48 hours
Day 30
Primary Efficacy Endpoint: Death or non fatal MI Primary Safety Endpoint: TIMI Major Hemorrhage
TNK: Tenecteplase; TPA: Tissue plasminogen activator; rPA: Reteplase; SK: Streptokinase; UFH: Unfractionated heparin; CrCl: Creatinine clearance
STEMI: ST-segment elevation myocardial infarction; MI:Myocardialinfarction; TIMI:Thrombolysis in Myocardial Infarction

51. ExTRACT-TIMI 25 Primary endpoint: Death or non fatal MI
8 days
Lost to follow up = 3 15
UFH
12.0% 12
9.3%
206 events
9.9% 9
5.2%
Enoxaparin
Primary Endpoint (%)
7.2% 6
EXTRACT-TIMI 25:
Enoxaparin versus UFH with Fibrinolysis for ST-Elevation Myocardial Infarction. Elliott M. Antman, et al. for the ExTRACT-TIMI 25 Investigators. N Engl J Med 2006;354: Fribrinolysis is the most common method of reperfusion used worldwide for patients with ST-elevation myocardial infarction. In addition, contemporary guidelines recommend the routine administration of unfractionated heparin. Despite receiving a fibrinolytic agent, aspirin and UFH, a substantial number of patients die or have another non-fatal myocardial infarction within one month after treatment. The use of UFH requires frequent monitoring to adjust the infusion rate to maintain a therapeutic range of anticoagulation
OBJECTIVES
To compare enoxaparin and UFH as adjunctive therapy for fibrinolysis in ST-elevation myocardial infarction
STUDY DESIGN
Prospective, randomized, double blind, multicenter, international trial,
Patients (N= 20,506) randomized to receive enoxaparin throughout the index hospitalization or weight-based UFH for at least 48 hours
Patient Inclusion criteria:
at least 20 minutes of ischemic symptoms while at rest within 6 hours ST-segment elevation or left bundle-branch block, and scheduled to undergo fibrinolysis
4.7%
RR: 0.83, (0.77–0.90)
p<0.0001
RR: 0.77
(0.71– 0.85) p<0.0001 3
RR: 0.90
(0.80–1.01) p=0.08 5 10 15 20 25 30
Days
*ITT: Intent-to-treat
Antman EM et al. for the ExTRACT-TIMI 25 Investigators. N Engl J Med 2006;354:

52. JAMA 2004

53. Innovative Idea!!!!

54. Fondaparinux Inhibits factor Xa and Thrombin STE ACS
less likely to cause HIT than UFH, LMWH
STE ACS
alternative to UFH in patients not undergoing reperfusion (Class 1) or receiving fibrinolytics (Class 2b)
not recommended for use alone in 1˚ PCI (Class 1a)
Schünemann HJ, Hirsh J, Guyatt G, et al. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133;

56. Fondaparinux
NSTE ACS
option for patients undergoing planned early angiography & revascularization with PCI
option for patients in whom an initial conservative strategy is planned
preferred agent for patients with high risk for bleeding (Class 1)

57. The OASIS 5 Study
OASIS 5
N Engl J Med 2006;354:

58. OASIS 5: A Randomized, Double-Blind, Double-Dummy Trial
20,078 Patients with NSTE ACS, Chest discomfort < 24 hours
2 of 3: Age>60, ST Segment Δ,  cardiac markers
Exclude
Age < 21
Any contra-ind to Enox
Hem stroke< 12 mo.
Creat> 3 mg/dL/265 umol/L
Aspirin, Clopidogrel, GPIIb/IIIa inhibitor, planned Cath/PCI as per local practice
Randomization
Fondaparinux
2.5 mg subcut daily up to 8 days or hospital discharge
Enoxaparin
1 mg/kg subcut bid for 2-8 days
1 mg/kg subcut daily if ClCr<30mL/min
Mean treatment : 5.4 days
Mean time to PCI: 2.4 days
Mean treatment : 5.2 days
Mean time to PCI: 2.6 days
Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
OASIS 5 Investigators. N Engl J Med2006;354:

61. OAISIS - 6

62. LMWH: Advantages More predictable anticoagulant response
Better bioavailability at low doses
Dose-independent clearance mechanism
Longer ½ life
Less binding to plasma proteins and to proteins released from activated platelets and endothelial cells
Less binding to endothelium
Less binding to macrophages

63. LMWH-Conclusion
Use of LMWH has been established as a first-line choice in the treatment of UA/NSTEMI
"increasing evidence suggests that it may supplant unfractionated heparin as an anticoagulant in the setting of PCI and STEMI."

64. Excellent Innovative Idea!!!!

65. Thrombin Inhibitors Weitz JI, Buller HR Circulation 2002;8:1004
Figure 1. Thrombin (IIa) interactions with fibrin. A, In addition to its active site, thrombin possesses 2 positively charged exosites; exosite 1 serves as the substrate-binding domain, whereas exosite 2 binds heparin. B, Thrombin binds to fibrin via exosite 1. By simultaneously binding to fibrin and exosite 2 on thrombin, heparin bridges thrombin to fibrin, thereby heightening the apparent affinity of thrombin for fibrin and inducing conformational changes at the active site of the enzyme. Because exosite 2 is occupied by the heparin molecule bridging thrombin to fibrin, antithrombin (AT)-bound heparin cannot bind to thrombin to form a ternary heparin/thrombin/AT complex. The conformational changes in the active site of thrombin may also limit access of AT to the active site of the enzyme. C, Active site-directed inhibitors, such as argatroban, inhibit fibrin-bound thrombin without displacing of the enzyme from fibrin, whereas bivalent inhibitors, such as hirudin or bivalirudin, displace thrombin from fibrin during the inactivation process.
Because thrombin plays a central role in arterial thrombogenesis, the goal of most treatment regimens is to block thrombin generation or inhibit its activity
Weitz JI, Buller HR Circulation 2002;8:1004

66. Direct Thrombin Inhibitors
Developed to overcome the inability of the heparin antithrombin complex to inactivate bound thrombin
Hirudin
Bivalirudin
Argatroban
Hirudin and argatroban approved in US for treatment of patients with HHT
Bivalirudin (Angiomax) approved as a heparin substitute in patients undergoing PCI

67. Direct Thrombin Inhibitors
Inhibit clot-bound & circulating thrombin
Does not bind plasma proteins
More predictable response than UFH
Antiplatelet activity
NSTE ACS
Bivalirudin: option in patients undergoing planned early angiography & revascularization (Class 1)

68. Direct Thrombin Inhibitors
ACUITY trial (Acute Catheterization and Urgent Intervention Triage StrategY)
Moderate to high risk patients with ACS undergoing invasive intervention (n=13,819) evaluated after 1 year
3 groups:
bivalirudin
bivalirudin + GP IIb/IIIa inhibitor
heparin/enoxaparin + GP IIb/IIIa inhibitor
Outcomes: death, MI, unplanned revascularization
White HD, Ohman EM, Lincoff AM, et al. Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) trial. J Am Coll Cardio. 2008;52(10):

69. Direct Thrombin Inhibitors
ACUITY results:
no difference in incidence of ischemic events or mortality at 1 year between the 3 regimens
43% relative risk reduction for major bleeding in bivalirudin monotherapy group at 30 days compared to UFH or enoxaparin + GP IIb/IIIa inhibitor
bilvalirudin alone can replace UFH or enoxaparin + GP IIb/IIIa inhibitor in moderate to high risk ACS patients undergoing PCI
White HD, Ohman EM, Lincoff AM, et al. Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) trial. J Am Coll Cardio. 2008;52(10):

70. 30 Day Mortality in ACUITY

71. Metaanalysis of contemporary Trials Bivalirudin alone vs UFH/Enox +GpIIb/IIIa
ACUITY- PCI
REPLACE II
PROTECT TIMI- 30

72. Concept of Biosimilarity

73. What are Biological Products ?
Definition:
Biologics are made from a variety of natural resources—human, animal, and microorganism—and may be produced by biotechnology methods.
Biological products can be composed of
sugars,
proteins, or
nucleic acids,
or a combination of these substances www. fda. gov

74. Concept of Biosimilarity
Biologics are made from a variety of natural resources—human, animal, and microorganism—and may be produced by biotechnology methods
Epoetin
Insulin
Growth hormone (GH)
Granulocyte colony stimulating factor (G-CSF)
Cytokines
Low Molecular Weight Heparins
Enoxaparin (e.g Clexane)
Dalteparin (e.g Fragmin)
Tinzaparin (e.g Innohep)

75. How do biologics differ from conventional drugs?
Most drugs consist of pure chemical substances and their structures are known.
On the other hand, biologics, however, are
complex mixtures
not easily identified or characterized.
Biological products differ from conventional drugs in as follows:
They
Are heat-sensitive and
Are susceptible to microbial contamination. (viral / bacterial)
Have a Complex manufacturing process hence process is the product
Have an Immunogenic Profile
This requires sterile processes to be applied from initial manufacturing steps.
FDA Food and Drug Administration

76. The heterogeneity of LMWH is very high, the mode of action is not completely understood and it is uncertain whether the PD markers are representative for the clinical outcome. Thus, the major burden of demonstrating two LMWHs being similar biological medicinal products is on a clinical trial.

77. NATF (North American Thrombosis Forum) Recommendations
SASAT (South Asian Society on Atherosclerosis & Thrombosis) Recommendations
LMWHs are biological agents and therefore cannot be True Generics. Some substandard products were also withdrawn due to compositional variations Efficacy and safety of biosimilar LMWH to originator LMWH to be demonstrated through prospective, randomized double blind versus originator to show noninferiority or therapeutic equivalence If a biosimilar does not satisfy the criteria defined for the full clinical trial or for the stringent pharmacokinetic assessments, it should therefore not be designated a biosimilar
NATF (North American Thrombosis Forum) Recommendations

79. Guidelines

81. ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS
Class I
Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy
Dose of UFH U/kg (max 5000) IV followed by infusion of U/kg/hr (initial max 1000 U/hr) titrated to aPTT times control
Dose of enoxaparin 1 mg/kg subcutaneously q12 hr; the first dose may be preceded by a 30-mg IV bolus
Class IIa
Enoxaparin is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours
The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding antithrombin therapy in patients with NSTE-ACS. The use of either unfractionated heparin (UFH) or a low molecular weight heparin (LMWH) is a class I recommendation. Based primarily on the ESSENCE and TIMI 11B studies, a class IIa recommendation was that enoxaparin was preferable to UFH. Whether this preferential recommendation changes as a result of the SYNERY study remains to be determined.
Available at:

82. Guidelines for the Use of Enoxaparin in Patients with NSTE-ACS
1 mg/kg SQ q12 hours (actual body weight)
An initial 30 mg IV dose can be considered
Adjust dosing if CrCl <30 cc/min
1 mg/kg SQ q24 hours
Do not follow PTT; do not adjust based on PTT
Stop if platelets  by 50% or below 100,000/mm3
If patient to undergo PCI:
0-8 hours since last SQ dose: no additional antithrombin therapy
8-12 hours since last SQ dose: 0.3 mg/kg IV immediately prior to PCI
Guidelines for the use of enoxaparin in patients with NSTE-ACS.

83. Guidelines - 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. (Box C1)
In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable. (Box C1) I
IIa
IIb
III A B I
IIa
IIb
III B
New Drugs
*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.

84. Guidelines - 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. I
IIa
IIb
III B
*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.

85. Guidelines – Anticoagulants in ACS
IIa
IIb
III A
b. If, after stress testing, the patient is classified as being at low risk (Box E2), the instructions noted below should be followed in preparation for discharge (Box K):
1. Continue ASA indefinitely. (Level of Evidence: A)
2. Continue clopidogrel for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)
3. Discontinue IV GP IIb/IIIa inhibitor if started previously. (Level of Evidence: A)
4. Continue UFH for 48 h or administer enoxaparin or fondaparinux for the duration of hospitalization, up to 8 d, and then discontinue anticoagulant therapy. (Level of Evidence: A)

86. 2007 Guidelines: Management of UA/NSTEMI patients undergoing an Initial Invasive Strategy

87. Key points In daily practice, you will
encounter diverse antithrombin therapies.
Current guidelines justify an array of
agents, depending on individual priorities.
• Workflow
• Concomitant antiplatelet therapy
• Cost
The penalties for switching are likely less
than once anticipated.

88. Do your choices effect outcomes?

89. Was it something I said?
Hope not!!!!!

90. Thank You for your attention

91. Time to Wakeup
FOR

92. Statistical Concerns with Noninferiority Trials

93. ACUITY Design

94. ACUITY Primary Analysis (N=9215)

95. Specification of Noninferiority Margin

96. ACUITY BLEEDING: ACUITY Major vs TIMI Major

97. Patient TIMI Risk Score (N = 13,819)

98. ACUITY Timing Analysis (N=9207)

99. Patients Treated Prior to Randomization

101. Bleeding Definitions

102. 2007 ACC/AHA Guideline Recommendations for UA/NSTEMI Undergoing PCI

103. 2007 update of ACC/AHA Guidelines for UA/NSTEMI

104. 2007 ACC/AHA Guideline Recommendations for UA/NSTEMI Undergoing PCI

106. ACC/AHA 2007 UA/NSTEMI Guidelines: Management of Patients with Elevated Risk