Download Direct Thrombin Inhibitor Pharmacology and Pharmacotherapy

Direct Thrombin Inhibitor
Pharmacology and
Pharmacotherapy
Mary Jane E. Mattern, PharmD
Pharmacist
William W. Backus Hospital
Learning Objectives
At the conclusion of this activity, participants will be
able to:
Discuss the pharmacology of the direct thrombin
inhibitors
Discuss the indications and contraindications for
the direct thrombin inhibitors
Thrombin Molecule
Personal Disclosure
There are no actual or potential conflicts of interest
associated with this presentation.
Approved Products in US
Argatroban
Hirudins: found in salivary glands of leeches (Hirudo
medicinalis)
Lepirudin: recombinant hirudin expressed in yeast
Bivalirudin: Synthetic analog of hirudin
Thrombin Molecule
Active site is set deep within groove, highly specific
binding
Exosite 1 = major binding site: fibrinogen, factor V,
protein C, thrombomodulin
Exosite 2 = heparin and heparan sulfate binding
1
Direct Thrombin Inhibitor
(DTI): Mechanism of Action
Act directly by binding to thrombin and blocking it’s activity
Argatroban binds non-covalently and reversibly to active site on
thrombin, no effect on exosites
Pharmacokinetics
Onset of action: Immediate
Metabolism:
Bind exosite 1 on thrombin molecule
Argatroban: hepatic via hydroxylation,
aromatization, and to a lesser extent CYP3A4/5
(metabolite formed in low amounts and is ~5 times
weaker than parent)
Bivalirudin forms reversible complex
Bivalirudin: blood proteases
Lepirudin forms irreversible complex
Lepirudin: catabolic hydrolysis
Hirudins inhibit thrombin bivalently
Bind active site on thrombin molecule
Pharmacokinetics
t1/2 Elimination
Argatroban: 40-50 minutes, impaired hepatic function lengthens up to 3
hours
Take a moment to reflect...
Among the 3 available DTIs,
which difference is most likely to
affect clinical care:
Bivalirudin: normal renal function = 25 minutes, CrCl 10-29 ml/min = 1 hour,
<10 ml/min = 3.5 hours
a) Argatroban only binds
active site on thrombin while
hirudins also bind exosites
Lepirudin: normal renal function = 10 minutes, impaired renal function
lengthens up to 2 days
b) Bivalirudin is metabolized
by blood proteases
Excretion
Argatroban: feces, urine
Bivalirudin: urine, proteolytic cleavage
Lepirudin: urine (35% as unchanged drug)
Contraindications
c) Lepirudin and bivalirudin’s
half lives are extended in renal
dysfunction
d) Argatroban is excreted in
the urine and feces
Indications
Argatroban:
Treatment and prevention of thrombosis in patients with heparin induced
thrombocytopenia
Hypersensitivity to drug or any component of
formulation
Active major bleeding
Adjunct to percutaneous coronary intervention (PCI) in patients with confirmed or
high risk of HIT
Bivalirudin:
Adjunct to percutaneous coronary intervention (PCI) in patients with confirmed or
high risk of HIT
In addition to aspirin in unstable angina patients undergoing percutaneous
transluminal coronary angioplasty (PTCA) or PCI with GPIIb/IIIa inhibitor
Lepirudin
Treatment of thrombosis secondary to HIT
2
Take a moment to reflect...
Which DTI is approved
for both the
prophylaxis AND the
treatment of
thrombosis associated
with HIT?
a) Argatroban
b) Bivalirudin
c) Lepirudin
HIT: Early vs. Delayed
Onset
Heparin Induced
Thrombocytopenia: Type 1 vs.
Type 2
HIT Type 1:
fall in platelet count within 2 days of initiation, then rebound
no clinical consequences
non-immune, probably due to heparin effects on platelet activation
HIT Type II
Immune mediated
Antibodies formed against heparin-platelet factor 4 complex
Thrombotic sequelae (venous and arterial)
Typical onset: Days 5-10 and 7-14 after exposure
HIT: Risk Factors
Early onset:
Median time from heparin exposure = 10.5 hours
Heparin preparation: bovine > porcine > LMWH
May be due to heparin exposure in past 3 months,
antibody formation
Patient diagnosis: post-surgical > medical > pregnant
Delayed onset:
Patient sex: female > male
Duration of exposure
Occurs 5-19 days after heparin exposure
Take a moment to reflect...
Which of the following
statements regarding HIT is
true?
a) Typical onset is within 10.5
hours of exposure
b) Risk of HIT in pregnancy is
> medical patients
c) HIT Type 1 is an immune
mediated reaction
d) HIT Type 2 is associated
with serious clinical
consequence of venous and
arterial thrombosis
CHEST Guidelines
Diagnostic recommendations:
Patients receiving or have received heparin within past 2 weeks, investigate
HIT diagnosis if platelet count falls by ≥ 50% and/or a thrombotic event
occurs between days 5 and 14 (even if patient is no longer receiving heparin)
(Grade 1C)
Treatment recommendations:
HIT suspected or confirmed +/- thrombosis: Recommend use of an
alternative, non-heparin anticoagulant (lepirudin-Grade 1C, argatroban-Grade
1C, fondaparinux-Grade 2C, bivalirudin-Grade 2C) (Grade 1B)
HIT suspected or confirmed: recommend against VKA therapy until platelet
count has recovered to at least 150K (Grade 1B)
HIT suspected or confirmed: recommend against LMWH (Grade 1B)
3
Argatroban Dosing
Initial dosing:
Intravenous continuous infusion of 2 mcg/kg/min
Use ABW up to 130 kg
Check aPTT in 2 hours and adjust until aPTT is 1.5-3 times baseline
(NTE 100 seconds or 10 mcg/kg/min)
Special populations:
Critically ill with multiple organ dysfunction (MOD), severe anasarca,
heart failure, post-cardiac surgery require dose reduction
Suggested starting dose in these patients: 0.5-1.2 mcg/kg/min
(Grade 2C)
Argatroban per Protocol
Take a moment to reflect...
RS, a 65 year old female was admitted
to the ICU 6 days ago for respiratory
failure. RS is on warfarin at home for
atrial fibrillation, but this was
discontinued on admission due to NPO
status. RS has been on IV heparin
infusion for anticoagulation since
admission. RS’s baseline platelet
count was = 400K, and today is 185K.
Due to large drop in platelet count, and
heparin exposure of 6 days duration,
HIT is highly suspected. Heparin is
immediately discontinued and the
attending physician asks for your
recommendation on what to do next...
Argatroban and VKA
Bridging
Thrombin (Factor II) affects PT/INR
Argatroban elevates PT/INR as well as aPTT
How do we know when INR target has been met?
Measure combined INR with argatroban and warfarin
Stop argatroban when combined INR > 4
Repeat INR in 4-6 hours, this is “true” INR
If subtherapeutic, restart argatroban
If in goal range, continue with VKA alone
Repeat daily until desired target achieved
Take a moment to reflect...
RS has been on
argatroban anticoagulation
while NPO, but is now
being transferred to the
medical floor and is able to
take oral medications. The
attending physician again
asks for your
recommendation on how to
transition RS back onto
warfarin. You give the
following
recommendations...
Direct Thrombin
Inhibitors...the Future of
Anticoagulation?
Heparin/warfarin:
Narrow TI
Variable dose response
requires frequent
monitoring
UFH binds non-specifically
to other sites (PF4,
endothelial cells, acute
phase reactants)
UFH cannot inactivate
thrombin or factor Xa within
a thrombus
4
Direct Thrombin
Inhibitors...the Future of
Anticoagulation?
DTI: the future?
1st must prove
Oral availability
Less need for
monitoring
Wider TI
Equivalent or better
efficacy
References
Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-Induced Thrombocytopenia." Annual Review of Medicine 61
(2010): 77-90.
“Argatroban.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters
(Healthcare) Inc.
Argatroban. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010.
“Bivalirudin.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters
(Healthcare) Inc.
Bivalirudin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010.
Franchini, Massimo. "Heparin-induced thrombocytopenia: an update." Thrombosis Journal 3.14 (2005): 1-5.51.
“Lepirudin.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters
(Healthcare) Inc.
Lepirudin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010.
The William W. Backus Hospital [internal protocol]. Argatroban protocol. Norwich, CT; rev 1/2009.
Warkentin, Theodore E., Andreas Greinacher, Andreas Koster, and A. Michael Lincoff. "Treatment and Prevention of
Heparin-Induced Thrombocytopenia." Chest 133 (2008): 340S-80S.
Zinkovsky, Daniel A., and Marilena S. Antonopoulos. "Heparin-Induced Thrombocytopenia: Overview and Treatment."
P&T 33.11 (2008): 642-
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