1
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 1
UC SF
New Anticoagulants and Critical Care
Linda Liu, M.D.
Professor
UCSF Dept of Anesthesia
University of California,San Francisco 2
UC SF
Difficult Task
• New anticoagulants
• 30 minutes
• Emphasis on 2 new oral anticoagulants – Dabigatran
– Rivaroxaban/Apixaban
University of California,San Francisco 3
UC SF
2
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 6
UC SF
Coagulation Cascade
Injury Clot
University of California,San Francisco 7
UC SF
Waterfall/ Cascade Model:1960’s Intrinsic Pathway
Extrinsic Pathway
Kallikrein
fXII
fXI
fIX
fVIII
Common Pathway
fX
fII
Fibrin
fVII
Tissue Factor
aPTT
PT
University of California,San Francisco 8
UC SF
Anticoagulants Historically
• Narrow therapeutic window
• Variable dose response among pts
• Interactions with drugs and diet
• Laboratory control needs to be
standardize
• Maintenance is difficult
3
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 9
UC SF
Waterfall/Cascade Model Intrinsic Pathway (aPTT)
Extrinsic Pathway (PT)
Kallikrein
fXII
fXI
fIX fVIII
fX
fII
Fibrin
fVII
Tissue Factor
Antithrombin
Heparin
(-) Warfarin
University of California,San Francisco 10
UC SF
Direct Thrombin Inhibitors Intrinsic Pathway (aPTT)
Extrinsic Pathway (PT)
Kallikrein
fXII
fXI
fIX fVIII
fX
fII
Fibrin
fVII
Tissue Factor
Antithrombin
Heparin
(-) Warfarin
DTI
University of California,San Francisco 11
UC SF
Direct Thrombin Inhibitors
Intravenous
• Hirudin
• Lepirudin
• Desirudin
• Argatroban
• Bivalirudin
University of California,San Francisco 12
UC SF
DTI - advantages
• Inhibit thrombin bound to fibrin (clot)
• Lack of required co-factor (AT)
• Predictable response
– Not bound to plasma proteins
– Not neutralized by PF4
• No induction of immune-mediated thrombocytopenia
4
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 13
UC SF
Thrombin Active
Site
Exo-
site
Thrombin Hirudin
Lepirudin
Thrombin
Bivalirudin
Argatroban
Thrombin
Nutescu et al, Cardiology Clinics, 26, New Anticoagulant Agents Direct Thrombin Inhibitors, 169-187, 2008.
With permission from Elsevier
University of California,San Francisco 14
UC SF
Intravenous DTI
• Monitor with aPTT or ACT
• FDA approval in HIT or PCI
• Fairly short acting
• Shown to work as well as heparin in
large cardiology trials for PCI
• Also lots of off-label uses
University of California,San Francisco 15
UC SF
Argatroban: other uses
• Ischemic stroke
• Hemodialysis and CVVH
• Peripheral vascular surgery
LaMonte et al, Stroke 2004;35:1677-82
Koster et al, J Thorac Cardiovasc Surg 2007;133:1376-7
University of California,San Francisco 16
UC SF
Bivalirudin: other uses
• CPB
• Vascular surgery
• Neuroendovascular procedures
Dyke et al, J Thorac Cardiovasc Surg 2006;131:533-9
Koster et al, Ann Thorac Surg 2007;83:572-7
Hallak et al, Cardiovasc Intervent Radiol 2007;30:906-11
Hassan et al, Neurocrit Care 2010
5
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 17
UC SF
Direct Thrombin Inhibitors
Lepirudin Argatroban Bivalirudin
HIT HIT/ PCI PCI
1.3 hr 40-50 min 25 min
Renal Hepatic Plasma/renal
$700 $1500 $800
INR + INR +++ INR +
University of California,San Francisco 18
UC SF
Direct Thrombin Inhibitors
Lepirudin Argatroban Bivalirudin
HIT HIT/ PCI PCI
1.3 hr 40-50 min 25 min
Renal Hepatic Plasma/renal
$700 $1500 $800
INR + INR +++ INR +
University of California,San Francisco 19
UC SF
Direct Thrombin Inhibitors
Intravenous
• Hirudin
• Lepirudin
• Desirudin
• Argatroban
• Bivalirudin
Oral
• Ximelagatran/
melagatran
• Dabigatran
University of California,San Francisco 20
UC SF
New DTI-Dabigatran etexilate
• Pradaxa®
• Approved by FDA 10/2010
• In Europe and Canada since 2008
• New oral anticoagulant in > 50 yrs!
• Half life: 12-17 hours
• Esterase metabolism to dabigatran
6
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 21
UC SF
Studies – Alphabet soup
• RE-NOVATE
• RE-MOBILIZE
• RE-MODEL
• RECOVER
• RE-LY
• ROCKET
• EINSTEIN
• EINSTEIN-
Extension
• MAGELLAN
• ARISTOTLE
University of California,San Francisco 22
UC SF
Dabigatran Indications
• VTE prevention after hip and knee
surgery
• Treat acute DVT/PE
• Cardiac events in ACS
• Prevent stroke and emboli in
nonvalvular AF
University of California,San Francisco 23
UC SF
Pharmacokinetics
• Low drug-drug or drug-food interactions
• No effect on cytochrome P450 enzymes
• 80% of drug is eliminated by kidneys
• Fixed 150 mg BID dose
University of California,San Francisco 24
UC SF
Dabigatran Monitoring Recs
• No monitoring is recommended except
elderly or renal failure patients
– Emergency surgeries
– Liver failure
– Concern about interaction with another
drug
– Bridging
Douxfils et al, J Thromb Haemost 107:5, 2012
7
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 25
UC SF
Dabigatran and PT
University of California,San Francisco 26
UC SF
Dabigatran and PTT
University of California,San Francisco 27
UC SF
Dabigatran and ECT
University of California,San Francisco 28
UC SF
Dabigatran and Thrombin Time
• Thrombin time is too
sensitive
• Linear with lower
concentrations
• Greatly prolonged at
higher levels
• Nl TT excludes the
presence of
significant drug
levels
Drug conc
>120 sec
8
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 29
UC SF
Case Report
• Participant in RE-LY undergoes CABG
• Drug stopped 2 days prior to OR, but pt
had CRI (CrCl 36 mL/min)
• Therapeutic on dabigatran
• Massive postoperative bleeding
Warkentin et al: Blood 119:9, 2173, 2012
Warketin et al, Blood, 119 (9), 2012
University of California,San Francisco 31
UC SF
Bleeding Events
• 5 fatal cases reported in Japan
• 260 fatal bleeding events worldwide
between March 2008 and October 2011
University of California,San Francisco 32
UC SF
Problems
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New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 34
UC SF
Circulation 2011;124:1573-1579
University of California,San Francisco 35
UC SF
Side Note on PCC
• Contain: prothrombin (II), VII, IX, X,
protein C and S
• 4 factor PCC contain VII – Cofact®
• 3 factor PCC do not contain VII – Bebulin®
– First 4 factor nonactivated PCC, just approved by
FDA (Kcentra® or Beriplex® in Europe)
University of California,San Francisco 36
UC SF
Dabigatran Reversal aPTT
10
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 37
UC SF
Dabigatran Reversal
University of California,San Francisco 38
UC SF
What does this mean?
• Unclear what relationship laboratory
tests have to clinical bleeding
• Are they surrogate markers for bleeding
tendency?
• Manufacturer recommends: – PCC - may be helpful in rats with tail incision
– rFVIIa - corrected rat tail bleeding time
– FFP - may be helpful in mice
University of California,San Francisco 39
UC SF
Dabigatran Reversals
• Dialysis: ~60% removed over 2-3 hours
• Oral activated charcoal may effectively
absorb drug after recent ingestion
Eriksson et al: J Thromb Haemost 1, 2490, 2003
University of California,San Francisco 40
UC SF
FXa Inhibitors Intrinsic Pathway (aPTT)
Extrinsic Pathway (PT)
Kallikrein
fXII
fXI
fIX fVIII
fX
fII
Fibrin
fVII
Tissue Factor
Antithrombin
Heparin
(-)
Fondaparinux
11
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 41
UC SF
Chromogenic Factor Xa assay
Xa
Xa
Substrate
Xa
Substrate
ATIII
Xa
fondaparinux
University of California,San Francisco 42
UC SF
FXa Inhibitors Intrinsic Pathway (aPTT)
Extrinsic Pathway (PT)
Kallikrein
fXII
fXI
fIX fVIII
fX
fII
Fibrin
fVII
Tissue Factor
Antithrombin (-)
Fondaparinux
fXa inhibitors
University of California,San Francisco 43
UC SF
Oral Xa inhibitors-Rivaroxaban
• Xarelto®
• Affects PT and PTT
somewhat
• Predictable
pharmacokinetics
• No monitoring
recommended
University of California,San Francisco 44
UC SF
Rivaroxaban
• FDA approval July 2011 for DVT
prophylaxis after hip/knee replacement
surgery
• FDA approval Sept 2011 for stroke
prophylaxis in Afib
12
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 45
UC SF
Rivaroxaban Testing
• Chromogenic anti-factor Xa assay
• Not yet available as rivaroxaban assay
• Not yet STAT lab
University of California,San Francisco 46
UC SF
Rivaroxaban Reversals
• No data on activated charcoal
• Is highly protein bound so unlikely that it
can be removed by hemodialysis
• No data on FFP in animal or human
studies
University of California,San Francisco 47
UC SF
Circulation 2011;124:1573-1579
University of California,San Francisco 48
UC SF
Rivaroxaban Reversal
13
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 49
UC SF
Rivaroxaban reversals
• PCC – Reduced PT in human volunteers
– Reversed prolonged BT in rats on high dose
rivaroxaban
• rFVIIa – Reduced rat mesenteric bleeding time
– Modest decrease in bleeding time in baboon
Fishman et al: Emerg Med J 25: 625-630, 2008
University of California,San Francisco 50
UC SF
Apixaban
• Eliquis®
• Approved for nonvalvular Afib – Dec
2012
• Half-life 8-15 hours
• Twice a day dosing
University of California,San Francisco 51
UC SF
Pt bleeding on dabigatran
or rivaroxaban therapy
Mild
Bleeding Moderate
Bleeding
Severe
Bleeding
Delay dose or
temporarily
discontinue
Local
control
measures
Supportive Rx
• Fluids
• FFP
• Monitoring
HD – dabigatran
PCC-rivaroxaban
rfVIIa
University of California,San Francisco 52
UC SF
Summary
• Exciting: clinical anticoagulant therapy
• Dissatisfying:
• Only INR standardized for warfarin
• Any other coagulation test used to
monitor any other anticoagulant lacks
standardization
14
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 53
UC SF
Withholding dabigatran
Renal Function Standard
Bleeding Risk
High Bleeding
Risk
CrCl > 50 mL/min Hold 24 hours Hold 2-4 days
CrCl 30-50
mL/min
Hold 2 days Hold 4 days
CrCl < 30 mL/min Hold 2-5 days Hold > 5 days
University of California,San Francisco 54
UC SF
Withholding rivaroxaban
Renal Function Standard
Bleeding Risk
High Bleeding
Risk
CrCl > 50 mL/min Hold 1-2 days Hold 3-4 days
CrCl 30-50
mL/min
No data No data
CrCl < 30 mL/min Do not use Do not use
University of California,San Francisco 56
UC SF
15
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 57
UC SF
Univ Washington Medical Center
University of California,San Francisco 58
UC SF
University of California,San Francisco 59
UC SF
Summary - dabigatran
• TT is sensitive test to ensure there is no
presence of dabigatran
• Back-up is normal aPTT – suggests
levels are low therapeutic or
subtherapeutic
University of California,San Francisco 60
UC SF
Summary - rivaroxaban
• Normal PT suggests low or no levels of
rivaroxaban
• Wait for anti-factor Xa activity assay for
rivaroxaban
16
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 61
UC SF
Summary – Massive Bleeding
• Supportive Care – fluid resuscitation,
compression, transfusion
• Discontinue Drug
• Activated charcoal for overdoses
• HD for dabigatran
• FFP not helpful – but fluid resuscitation
• rFVIIa/PCC - ? Unknown effect on
clinical bleeding
Kaatz et al: Am J Hematol, March, 2012
University of California,San Francisco 62
UC SF
Coagulation, Blah, Blah,
Blah,Blah, Blah,
Blah, Blah, Blah, Blah,
Blah,…..zzZZ
University of California,San Francisco 63
UC SF
Injury Clot
Coagulation Cascade
University of California,San Francisco 64
UC SF
Coagulation Cascade Intrinsic Pathway
Extrinsic Pathway
Kallikrein
fXII
fXI
fIX
fVIII fX
fII
Fibrin
fVII
Tissue Factor
17
New Anticoagulants and Critical Care Linda Liu, M.D.
University of California,San Francisco 65
UC SF
Coagulation Cascade Intrinsic Pathway (aPTT)
Extrinsic Pathway (PT)
Kallikrein
fXII
fXI
fIX fVIII
fX
fII
Fibrin
fVII
Tissue Factor
Antithrombin
Heparin
(-) Warfarin
Fondaparinux
fXa inhibitors
DTI
University of California,San Francisco 66
UC SF
Questions?
