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80 Anticoagulation Therapy
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TABLE 4-12: Dosing and Monitoring Considerations for LMWH
and Fondaparinux in Renal Impairment
Anticoagulant Pharmacokinetic
Considerations
Dalteparin CrCl <30 mL/
min
b
: No
accumulation
noted up to 1
week of therapy.
CrCl 30–50
mL/min: No
accumulation
noted.
Enoxaparin CrCl <30 mL/
min
b
: 40−50%
accumulation
noted
CrCl 30–50 mL/
min: 15−20%
accumulation
noted.
Dosing and Monitoring
Recommendations
CrCl <30 mL/min
No dose adjustment
needed up to 1 week
with prophylaxis doses;
for treatment doses,
consider monitoring
anti-Factor Xa activity.
For use >1 week:
Consider monitoring of
anti-Factor Xa activity
and adjust dose if
accumulation is noted.
CrCl 30–50 mL/min:
No dose adjustment
needed.
CrCl <30 mL/min
Consider a 40−50%
dose decrease and
subsequent monitoring
of anti-Factor Xa
activity.
CrCl 30–50 mL/min:
Consider a 15−20%
dose decrease with
prolonged use (>10–14
days) and subsequent
monitoring of antiFactor Xa activity.
a
Package Insert
Recommendations
b
:
CrCl <30 mL/minb: Use with
caution.
b
:
CrCl 20–30 mL/minb:
Prophylaxis, 30 mg sub-Q
daily; treatment, 1 mg/
kg sub-Q daily. See below
for CrCl <20 requiring
hemodialysis.
b
Fondaparinux CrCl <30 mL/
b
: 55%
min
accumulation
noted.
CrCl 30–50
mL/min: 40%
accumulation
noted.
CrCl <30 mL/min:
Contraindicated in this
population.
CrCl 30–50 mL/
min: If prolonged
use (>10 days), drug
accumulation may occur
and dosing adjustment
may be necessary.
Could consider
measurement of
anti-Factor Xa activity
to guide with dose
adjustment.
CrCl <30 mL/min:
Contraindicated.
CrCl 30–50 mL/min: Use with
c
caution.
(continued)
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 81
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TABLE 4-12: (Continued)
a
The use of an anti-Factor Xa activity measurement to adjust dosing in the setting of renal
insufficiency has not been validated, and it is at best a controversial practice. Trough anti-FactorXa activity measurements have been considered to assess potential accumulation in patients at
increased risk for bleeding.
b
Data are very limited in patients with a CrCl <20 mL/min. In patients on hemodialysis, limited
data are only available for thrombosis prevention in the dialysis circuit but not for the prevention
and/or treatment of venous or arterial thrombosis. UFH is the agent of choice in patients
on hemodialysis or with a CrCl <20 mL/min. In one comparative single center assessment,
enoxaparin 0.6–0.7 units/kg daily (range 0.4−1 units/kg with no measuring of anti-Factor Xa
activity) was safe and effective in transitioning patients requiring hemodialysis to warfarin.17 CrCl
measurements in the clinical trials may have used total body weight and, thus, estimate a value
higher than estimated when using the ideal body weight.
c
Care should be exercised when fondaparinux is used for an extended time (>7–10 days) in
patients with moderate renal impairment (CrCl 30–50 mL/min, as accumulation of the drug has
also been reported in these patients at a rate of approximately 40%).
CrCl: creatinine clearance, sub-Q: subcutaneous
• LMWHs are preferred over warfarin, UFH,
and fondaparinux for acute and chronic
anticoagulation in the setting of cancer-related
thrombosis. Benefits are primarily seen in nonmetastatic disease.
Dosing Considerations in the Elderly
•
Before sending an elderly patient home on a LMWH or fondaparinux, consider
dexterity, eyesight, and ability to self-inject.
•
In addition to age, renal function and weight change over time. See dosing and
monitoring considerations above.
•
Dosing strategies of enoxaparin 1 mg/kg twice
daily or dalteparin 200 units/kg once daily
during the first 4 weeks have been suggested to
provide a more aggressive level of anticoagulation
when the risk of recurrent thrombosis is the
greatest.
Dalteparin is the only LMWH with an FDA-
•
approved indication for treatment of venous
thrombosis in the setting of cancer.
• Benefits of efficacy or safety of LMWH use
beyond 6 months have not been established at
this time.
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Dosing Considerations in Critically Ill Patients
•
Bioavailability for LMWH can be reduced in the setting of edema, hypotension,
or active vasopressor use.
(i.e., large trauma, renal failure), thereby reducing the level of anticoagulation.
Anti-Factor Xa activity measurements using an assay that incorporates antithrom
bin may not identify it (see Chapter 21).
•
No clear data exist on guiding subsequent dose adjustments for these situations.
REFERENCES AND KEY ARTICLES*
*1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrom-
botic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest
Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):
e24S-e43S.
2. Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-699.
3.
Haines ST, Witt D, Nutescu EA. Venous thromboembolism. In: DiPiro J, Talbert R, Yee
G, et al. eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY:
McGraw-Hill; 2008:331-372.
*4.
Nutescu EA, Dager W. Heparin, low molecular weight heparin, and fondaparinux. In:
Gulseth M, ed. Managing Anticoagulation Patients in the Hospital. Bethesda, MD:
ASHP; 2007:177-202.
Nutescu EA, Haines ST, Wittkowsky AK. Venous thromboembolism. In: Chisholm-Burns
5.
M, Schwinghammer T, Wells B, et al., eds. Pharmacotherapy Principles and Practice.
4th ed. New York, NY: McGraw-Hill; 2016:163-192.
6.
Hirsh J, O‘Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin:
current and future advances. Circulation. 2007;116(5):552-560.
Lovenox [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2013. http://products.
7.
sanofi.us/lovenox/lovenox.html. Accessed March 19, 2017.
8. Fragmin [package insert]. New York, NY: Pfizer; 2015. http://labeling.pfizer.com/
ShowLabeling.aspx?id=2293. Accessed March 19, 2017.
9. Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009. http://
www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf. Accessed
March 19, 2017.
10. Nutescu EA, Wittkowsky AK, Dobesh PP, et al. Choosing the appropriate antithrombotic
agent for the prevention and treatment of VTE: a case-based approach. Ann
Pharmacother. 2006;40:1558-1571.
11. Linkins LA, Dans AL, Moores LK, et al. Antithrombotic Therapy and Prevention of
Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical
Practice. Chest. 2012; 141(2)(suppl 2):e495S-e530S.
12. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient
receiving antithrombotic or thrombolytic therapy. Reg Anesth Pain Med. 2010;35:64-
101.
13. Lim W, Dentali F, Eikelboom JW, et al. Meta-analysis: low-molecular-weight
heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med.
2006;144:673-684.
-
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 83
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14. Monagle P Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest.
2001;119 (suppl 1):344S-370S.
*15. Laposata M, Green D, Van Cott EM, et al. College of American Pathologists Conference
XXXI on Laboratory Monitoring of Anticoagulant Therapy: the clinical use and
laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and
related compounds, and argatroban. Arch Pathol Lab Med. 1998;122:799-807.
Nutescu EA, Spinler SA, Wittkowsky AK, et al. Low molecular weight heparins in renal
*16.
impairment and obesity: available evidence and clinical practice recommendations
across medical and surgical settings. Ann Pharmacother. 2009;43:1064-1083.
17.
Pon TK, Dager WE, Roberts AJ, White RH. Subcutaneous enoxaparin for therapeutic
anticoagulation in hemodialysis patients. Thromb Res. 2014;133:1023-8.
https://t.me/med1917
5
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Chapter
PARENTERAL DIRECT THROMBIN
INHIBITORS
William E. Dager and A. Joshua Roberts
INTRODUCTION
The parenteral direct thrombin inhibitors (DTIs) act independent of antithrombin
and are typically used in situations where unfractionated heparin (UFH) is not
recommended or contraindicated such as heparin-induced thrombocytopenia,
antithrombin deficiency, or in the setting of acute coronary syndromes. This class
of agents works differently than other anticoagulants, despite similar laboratory
assessments. Further, due to more limited experience with their use, it is important
to approach their management and laboratory assay target ranges as independent
of observations with other anticoagulants. There are currently two parenteral DTIs
available in the United States—bivalirudin and argatroban. Lepirudin and desirudin
are no longer available.
PHARMACOLOGY
•
The activity of thrombin can be inhibited by currently available DTIs that bind directly
to either the catalytic (active) site or substrate recognition site (exocite 1). Thrombin
also contains a heparin-binding site (exocite 2).
•
All commercially available DTIs directly bind to the catalytic (active) site on thrombin
responsible for enzymatic activity.
•
Binding to the catalytic (active) site on thrombin inhibits several actions of thrombin
including cleavage of fibrinogen and platelet activation, both of which are involved
in thrombus formation.
•
Bivalent DTIs (bivalirudin, desirudin, and lepirudin) also bind to the substrate recognition (exocite 1) on thrombin where fibrinogen can bind.
•
DTIs do not bind to exocite 2, and thus are capable of inhibiting the effects of thrombin
bound to fibrin (clot bound thrombin).
•
DTIs can also block thrombin’s ability to activate platelets as well as stimulate granule
release, surface receptor expression and aggregation, and a plethora of other factors
that mediate vascular integrity.
•
Lepirudin and desirudin are able to tightly bind to thrombin and can lead to prolonged
inhibition. These agents are no longer available.
•
Bivalirudin is enzymatically cleaved by thrombin. This results in loss of activity that is
primarily independent of renal or hepatic function. Its effects may not last in stagnant
1-2
85
86 Anticoagulation Therapy
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blood. Increased elimination can occur with hemofiltration.
•
The onset of bivalirudin on activated clotting time (ACT) values occurs within
5–10 minutes after a bolus.
•
Dabigatran etexilate is an oral DTI (see Chapter 7 for further details).
•
See Table 5-1 for further pharmacokinetic/pharmacodynamics information.
PHARMACOKINETICS/PHARMACODYNAMICS
TABLE 5-1: Pharmacokinetics of Available Parenteral Direct
Thrombin Inhibitors
Agent Argatroban Bivalirudin
Source Synthetic Analog of hirudin
Route of administration IV IV
Plasma half-life (healthy subjects) 31–51 min 25 min
Primary elimination route Hepatic Enzymatic
Fraction excreted unchanged in the urine 16% 20%
Effect on INR
(depends on the amount of DTI present; this may
correlate to an elevation in the aPTT or ACT level in the
sample)
ACT: activated clotting time, aPTT: activated partial thromboplastin time, IV: intravenous, min:
minutes
Parenteral DTIs are most commonly used in acutely ill patients who may have reduced organ
function and elimination.
Time to steady-state may take longer, and effects may last more than a few hours after stopping
the infusion.
3-5
Moderate Mild
DOSING/ADMINISTRATION
•
Post-marketing experiences have suggested lower dosing approaches than those
used in clinical trials, especially in acutely ill patients.
•
The initial dosing regimen for a DTI will depend on the indication for anticoagulation, clinical presentation of the patient, and the desired intensity of parenteral
anticoagulation, similar to how heparin is utilized (Tables 5-2, 5-3, and 5-4).
•
Specific factors that may influence the dosing and target ranges include the
following:
Presence of thrombosis, acute thrombosis—consider higher doses
with aPTT target ranges of 2–2.5x normal baseline initially (2–3x
normal baseline for argatroban).
Note: The higher aPTT target for argatroban is based on the targets
set in the original ARG 911 trial. No trial was done for bivalirudin
in heparin-induced thrombocytopenia (HIT); however, published
single-center experiences in over 1,000 individuals typically follow
PARENTERAL DIRECT THROMBIN INHIBITORS 87
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the 1.5–2.5 x normal baseline aPTT as set in the lepirudin heparinassociated thrombocytopenia (HAT) trials.
Presence of active bleeding or risk factors for bleeding—consider
lower doses or use the lower end of the aPTT target range (1.5−2
for bivalirudin or 1.5−2.5 x normal baseline for argatroban 2 x
normal baseline).
•
Note that ACT readings with a DTI may vary between low and high response
assay methods.
•
For argatroban, there is poor correlation between the aPTT and hemoclot
thrombin inhibitor assay. When using assays independent of methods used in
trials, consider if improved accuracy of measuring the agent has an impact on
actual outcomes for bleeding or thrombotic complications.
6,7
TABLE 5-2: Dosing and Administration of DTIs for Selected
Indications
Indications Argatroban
HIT: typical IV dosing
(See Chapter 15)
3,5,8-16
• Has FDA indication
No bolus
•
•
Prescribing information:
2 mcg/kg/min
Average dose in trials 1.6
•
mcg/kg/min. Subsequest
published experiences
have observed doses
lower than 2 mcg/kg/min
in general. Rarely used at
rates >3 mcg/kg/min.
• Maximum dose 10 mcg/
kg/min
In acutely/critically ill
•
patients, starting doses
of 0.5–1.2 mcg/kg/min
have been used.
• Reduce dose in hepatic
failure.
• aPTT target 1.5–3 x
baseline. Maximum of
100 sec.
Bivalirudin
• No FDA indication in HIT.
Multiple single center
experiences published.
The approved dose
listed in the prescribing
information is in ACS,
which is much higher
than used in HIT.
• Typically no bolus
Bolus: 0.2 mg/kg (in
cases of life-/limbthreatening thrombosis)
• Starting doses:
CrCl >60 mL/min:
0.12–0.15 mg/kg/hr
• aPTT target 1.5–2.5 x
control
(continued)
88 Anticoagulation Therapy
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TABLE 5-2: (Continued)
Indications Argatroban
Bivalirudin
ACS/PCI/PTCA
Avoid drawing INR values
during the use of these higher
doses as high false positive
values will occur.
• Bolus: 350 mcg/kg IV
Infusion: 25 mcg/kg/min
•
IV dosing
•
Low Range ACT target:
300–450 sec
If low range ACT
•
<300 sec, can consider
adjusting upward to as
high as 40 mcg/kg/min
If ACT >450, consider
•
adjusting infusion rate as
low as 15 mcg/kg/min
With GPIIb/IIIa inhibitors:
•
250 mcg/kg IV bolus
followed by an infusion
of 25 mcg/kg/min
IV targeting ACT of
275–450 sec; for ACT
<275 sec, a 150-mcg/kg
IV bolus is given.
Pre-PCI (early invasive
strategy)
•
Bolus: 0.1 mg/kg IV
•
Infusion: 0.25 mg/
kg/hr IV until PCI or
angiography
PCI
• Bolus: 0.75 mg/kg IV
No adjustment needed if
•
CrCl >29 mL/min
•
0.5 mg/kg IV if receiving
pre-PCI infusion
Infusion: 1.75 mg/kg/
•
hr IV (CrCl ≥30 mL/min)
for up to 4 hours post
procedure (CrCl 15–29
mL/min: 1 mg/kg/hr)
Post-PCI (continued infusion)
• 0.2 to 0.25 mg/kg/hr IV
for up to 12 to 20 hours
post PCI
•
Removal of closure
device, with a aPTT
target of approximately
65–70 sec
• ACT target: None
CrCl <30 mL/min:
•
1 mg/kg/hr IV
•
Dialysis: 0.25 mg/kg/hr IV
14
13
Unstable angina • N/A • Infusion: 0.2 mg/kg/hr IV
ACS: acute coronary syndrome, ACT: activated clotting time, aPTT: activated partial
thromboplastin time, CrCl: creatinine clearance, FDA: U.S. Food and Drug Administration, HIT:
heparin-induced thrombocytopenia, hr: hour, INR: international normalized ratio, IV: intravenous,
kg: kilograms, mcg: micrograms, min: minutes, N/A: not applicable, PCI: percutaneous coronary
intervention, PTCA: percutaneous transluminal coronary angioplasty, sec: seconds, x: times
PARENTERAL DIRECT THROMBIN INHIBITORS 89
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TABLE 5-3: Renal, Hepatic, and Hepatorenal Failure
Anticoagulation Dosing under HIT Conditions
Modifying
Argatroban
Factor
Hepatic dose
•
Child-Pugh score >6 (see
adjustments
• Reduce dose to less than or
Renal dose
Renal dysfunction dose
•
adjustments
(Hemodialysis
See Table 5-4)
No apparent effect of HD on
•
•
A dosing decrease of 0.1–0.6
Hepatorenal
dose
adjustments
Monitoring
• Prolonged effects
Start with low dose then titrate
•
•
Assume initial aPTT is not
•
1.5–3 x control
goal aPTT
a
Argatroban is generally preferred over lepirudin in severe renal failure. Bivalirudin may have
pharmacokinetic advantages in concurrent hepatic and renal failure.
b
Use patient’s baseline aPTT value as the control. The institution’s mean aPTT value can be used if
there is no baseline value.
aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, HD: hemodialysis, HIT:
heparin-induced thrombocytopenia, x: times
a
Chapter 11) or total bilirubin
equal to 0.5 mcg/kg/min
adjustment unclear. Reduced
elimination observed in renal
impairment may be from the
kidney influencing selected
metabolic pathways.
elimination
mcg/kg/min for every 30-mL/
min drop in CrCl in HIT has
been reported.
up
steady state
b
Bivalirudin
• Eliminated enzymatically
Eliminated enzymatically and
•
• Removed by hemodialysis and
•
CrCl >60 mL/min: 0.12–0.15
CrCl 30–60 mL/min: 0.08–0.1
•
CrCl <30 mL/min: 0.05–0.08
•
•
Substantially removed during
Eliminated enzymatically and
•
• 1.5–2.5 x control
3,15-19
and may only need minor
adjustment for hepatic function.
may not need large adjustment
for renal dysfunction alone.
(Critically ill may require doses
on lower end of the range.)
ultrafiltration
mg/kg/hr
(range 0.06–0.13 reported)
mg/kg/hr
mg/kg/hr
HD
may not need major adjustment
for hepatic function.
b
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