Which Anticoagulant and For How Long

1
Which Anticoagulant and For How Long?

• John Eikelboom

Chair Harvey White
2
Ischaemic Heart Disease World Rank Order of
Disease Burden (DALY)
2020
1990
Lower resp infection Diarrhoeal
diseases Perinatal Major depression Isch heart
disease Cerebrovasc diseas TB Measles Traffic
accidents Cong anomalies Malaria COPD Falls Fe-def
anaemia Prot-energy malnut
1 Isch heart disease 2 Major depression 3
Traffic accidents 4 Cerebrovasc disease 5
COPD 6 Lower resp infection 7 TB 8 War 9
Diarrhoeal diseases 10 HIV 11 Perinatal 12
Violence 13 Cong anomalies 14 Self-inflicted
injuries 15 Bronchial and lung CA
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
16 17 19 28 33
19 24 25 37 39
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Acute Coronary SyndromesWhich Anticoagulantand
for how long?

• Pathophysiology of ACS what are we targeting
  with anticoagulant therapy?
• Which heparin should we use? Unfractionated or
  low-molecular-weightand, if the latter, which
  one?
• How long should heparin be continued?
• Are there more effective and safer alternatives
  to heparin?
• Is there a role for warfarin?
• New anticoagulant drugs

4
Yeghiazarians Y, et al. N Engl J Med 2000 342
101-114.
5
CV RISK FACTORS smoking hypertension
diabetes hypercholesterolemia sheer stress
infection? high homocysteine?
ENDOTHELIAL DYSFUNCTION
INFLAMMATION
NFk B
PLAQUE RUPTURE
? Nitric oxide, PGI2, TGF ? Adrenomedullin, CNP ?
Endothelin-1, PDGF, ACE
? Adhesion molecules (ICAM, VCAM) ? ?
Interleukins (IL-6), CRP ? Apoptosis, Tissue
Factor
VASOCONSTRICTION, PLATELET ACTIVATION, THROMBIN
GENERATION
ACUTE CORONARY SYNDROME
Corti R, Fuster V, Badimon J. J Am Coll Cardiol
2003 41 7S-14S.
6
Pathophysiology of ACS?Central Role of Thrombin
Plaque rupture
Platelet activation
Coagulation activation
Activated platelet
Factor V, VIII, XI
Platelet thrombin receptor
THROMBIN
FXIII activation
TAFI activation
Fibrin formation
Fibrin X-linking
? clot lysis
7
LMW Heparin
Unfractionated Heparin
Warfarin
Thrombin
Direct Thrombin Inhibitors
Selective Factor Xa Inhibitors
Novel Agents
8
Which Heparin? Unfractionated and LMW Heparin
UFH mean 50 saccharide units
LMWH mean 18 saccharide units
Fondaparinux 5 saccharide units
9
Which Heparin?Pharmacological Effects of Shorter
Chains

• More selective anti-Xa activity
• upstream blockade of coagulation pathway
• uncertain clinical importance
• Less non-specific tissue binding
• predictable anticoagulant effect
• fixed weight-determined dose
• long half life allowing once or twice daily
  administration
• Less platelet binding
• lower risk of heparin-induced thrombocytopaenia
• lower risk of osteopenia

10
Coagulation pathways
Anticoagulants
Tissue factor / factor VIIa
NAPc2 TFPI
Initiation
F X
F IX
(extrinsic)
(intrinsic)
UFH
F IXa F VIIIa
Warfarin
Thrombin generation
UFH, LMWH Fondaparinux Oral Xa inhibitors
F Xa F Va
UFH, LMWH Hirudin, Bivalirudin Ximelagatran
Thrombin activity
Thrombin
11
Coagulation pathways
Anticoagulants
Tissue factor / factor VIIa
NAPc2 TFPI
Initiation
F X
F IX
(extrinsic)
(intrinsic)
UFH
F IXa F VIIIa
Warfarin
Thrombin generation
UFH, LMWH Fondaparinux Oral Xa inhibitors
F Xa F Va
UFH, LMWH Hirudin, Bivalirudin Ximelagatran
Thrombin activity
Thrombin
12
Which Heparin? Effect of Chain Length
differences
Weitz J, et al. N Engl J Med 1997
13
Which Heparin? Effect of Chain Length
differences
Weitz J, et al. N Engl J Med 1997
14
Which Heparin?LMWHs also of Differing Chain
Length
Weitz J, et al. N Engl J Med 1997
15
Which Heparin?Short Term UFH vs. Control
(Death?MI)
Oler A, et al. JAMA 1996 276 811-5.
16
Which Heparin?Short Term LMWH vs. Placebo
(Death/MI)
FRISC Investigators. Lancet 1996 347 561-8.
17
Which Heparin? Short Term LMWH vs. UFH (Death/MI)
Eikelboom et al. Lancet 2000 355 1936-42
18
Which Heparin?Short Term LMWH vs. UFH
(Death/MI/RI)
Braunwald E, et al. ACC/AHA Guidelines 2002
19
Which Heparin?Benefit in High Risk Patients
(Death/MI)
Lindahl B, et al. J Am Coll Cardiol 1997 2938
979-86. Morrow DA, et al. J Am Coll Cardiol 2001
36 1812-7.
20
How Long?Long Term LMWH vs. Placebo (Death/MI)
Eikelboom et al. Lancet 2000 355 1936-42
21
How Long?Long Term LMWH vs. Placebo (Death/MI)
FRISC II investigators. Lancet 1999 354
701-7. Lindahl B, et al. J Am Coll Cardiol 2001
38 979-86.
22
How Long?Long Term LMWH vs. Placebo (Death/MI)
Antmann E, et al. Circulation 1999 199 1593-601.
23
How Long?Long Term LMWH vs. Placebo (Major
Bleeds)
Eikelboom et al. Lancet 2000 355 1936-42
24
Which Heparin and How Long?Summary

• UFH reduces death/MI by about 30
• LMWH at least as effective and safe as UFH
• UFH dosing?1
• 10-20 better?
• Particular benefit in high risk subgroups (cTn)
• No benefit of continuing treatment beyond about
  one week

1. Raschke R, et al. Ann Intern Med 2003 138
720-3.
25
Unresolved IssuesLong Term Rx, GPIIb/IIIa
inhibitors, PCI

• Long term treatment
• High risk patients (FRISC II)?
• Combination with GPIIb/IIIa inhibitors and
  thienopyridines
• A to Z trial (n4000)
• During Percutaneous Coronary Intervention in
  combination with GP IIb/IIIa inhibitors
• SYNERGY trial (n8000)

26
Unresolved IssuesGPIIb/IIIa Inhibitors
Enoxaparin used except in GUSTO IV and PARAGON.
GUSTO IV Dalteparin Substudy only 646 received
LMWH. Various LMWH preparations used Only 411
received LMWH
27
LMW Heparin
Unfractionated Heparin
Warfarin
Thrombin
Direct Thrombin Inhibitors
Selective Factor Xa Inhibitors
Novel Agents
28
Direct Thrombin InhibitorsAdvantages over Heparin
Eikelboom JW, et al. J Am Coll Cardiol 2003 41
70S-78.
29
Thrombin
amplification
Heparin-AT III
Direct Thrombin Inhibitor
30
Coagulation pathways
Anticoagulants
Tissue factor / factor VIIa
NAPc2 TFPI
Initiation
F X
F IX
(extrinsic)
(intrinsic)
UFH
F IXa F VIIIa
Warfarin
Thrombin generation
UFH, LMWH Fondaparinux Oral Xa inhibitors
F Xa F Va
UFH, LMWH Hirudin, Bivalirudin Ximelagatran
Thrombin activity
Thrombin
31
Direct Thrombin InhibitorsMost Widely Studied
Agents
Weitz JI, et al. Circulation 2002 105 1004-11.
32
Direct Thrombin InhibitorsAcute Coronary
Syndromes
Direct Thrombin Inhibitor Trialists
Collaboration. Lancet 2002 359 294-302.
33
Direct Thrombin InhibitorsHERO-2
(Death/Disabling Stroke/Re-MI
White HD, et al. Lancet 2002
34
Direct Thrombin InhibitorsREPLACE Trial in PCI
Bivalirudin versus UFH plus GP IIb/IIIa inhibitor
Lincoff M, et al. JAMA 2003 289 853-63.
35
Direct Thrombin InhibitorsSummary and Unresolved
Issues

• Superior to UFH, not compared with LMWH
• Increased bleeding with Hirudin, reduced with
  Bivalirudin
• Hirudin largely evaluated prior to the era of
  stents, glycoprotein IIb/IIIa inhibitors,
  thienopyridines
• Bivalirudin non-inferior to UFH during PCI, less
  bleeding

36
Anticoagulation - How Long?Rebound Thrombin
Generation
Dalt vs. UFH (n71)
Bijsterfeld N, et al. J Am Coll Cardiol 2002 39
811-7.
37
Anticoagulation - How Long?Persistent Long Term
Thrombin Generation
(n400)
Eikelboom JW, et al. Eur Heart J 2002 23 1771-9.
38
Coagulation pathways
Anticoagulants
Tissue factor / factor VIIa
NAPc2 TFPI
Initiation
F X
F IX
(extrinsic)
(intrinsic)
UFH
F IXa F VIIIa
Warfarin
Thrombin generation
UFH, LMWH Fondaparinux Oral Xa inhibitors
F Xa F Va
UFH, LMWH Hirudin, Bivalirudin Ximelagatran
Thrombin activity
Thrombin
39
WarfarinOASIS Trial (n3,712)
MI/Stroke CV Death
OASIS Investigators. J Am Coll Cardiol 2001 37
475-84.
40
Warfarin ASPECT Trial (n999)
MI/Stroke Death
van Es RF, et al. Lancet 2002 360 109-13.
41
Warfarin in CADModerate Intensity ASA versus
ASA
Anand S, et al. J Am Coll Cardiol 2003 41
62S-69S.
42
Optimal Duration of AnticoagulationWarfarin

• Efficacy
• Non-ST-elevation ACS
• ASPECT
• ATACS pilot / main
• OASIS pilot / main
• ST-elevation MI
• ASPECT
• CHAMP
• WARIS

• Safety
• Major Bleeding
• Intracranial Bleeding
• Inconvenience
• Physicians
• Patients

43
Coagulation pathways
Anticoagulants
Tissue factor / factor VIIa
NAPc2 TFPI
Initiation
F X
F IX
(extrinsic)
(intrinsic)
UFH
F IXa F VIIIa
Warfarin
Thrombin generation
UFH, LMWH Fondaparinux Oral Xa inhibitors
F Xa F Va
UFH, LMWH Hirudin, Bivalirudin Ximelagatran
Thrombin activity
Thrombin
44
Emerging Anticoagulant StrategiesPentasacharide
(Fondaparinux)
Gallus AS, et al. Curr Opin Hematol 2002 9
422-9.
45
Emerging Anticoagulant StrategiesPENTUA Results
n1000
Simoons ML, et al. Circulation 2001 104 1b4b
Abstract.
46
SummaryWhich Anticoagulant and For How Long?

• LMWH replacing UFH as new standard of care
• At least as effective, less S/E, more convenient
• Particular benefit in high-risk patients
• Emerging data supporting safety with GPIIb/IIIa
• Further data awaited re LMWH in PCI (SYNERGY)
• LMWH continued beyond 1 week is not of benefit
• Unfractionated heparin
• extremes of weight, renal failure, high bleed
  risk
• ?PCI, pre-CABG

47
SummaryWhich Anticoagulant and For How Long?

• Direct thrombin inhibitors
• Superior to UFH not compared with LMWH
• HIT patients
• Bivalirudin in PCI
• Warfarin
• Effective but not routinely recommended
• Limited by bleeding risk, inconvenience (poor
  compliance)
• Novel agents fondaparinux, ximelagatran

48
ACC/AHA Guidelines 2002
49
Non-ST-Elevation ACSComponents of the TIMI Risk
Score
Sabatine MS, et al. J Am Coll Cardiol 2003 41
89S-95S.
50
The Risk-Benefit Favours Heparin With
Thrombolysis Collins Meta-analysis
51
ST-Elevation Myocardial InfarctionWhich
Anticoagulant and For How Long?

• UFH
• Alteplase treated patients(Class IIa indication)
• LMWH
• Efficacy - emerging data (ASSENT 3)
• Safety excess bleeding (pre-hospital, gt75 y.o.)
• ExTRACT-TIMI 25, CREATE (total ngt40,000)
• DTI
• Superior to UFH, further evaluation with
  alteplase
• Warfarin