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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
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200 Anticoagulation Therapy
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AGENT-SPECIFIC CONSIDERATIONS
Unfractionated Heparin
•
The half-life is relatively short (60–90 minutes) with effects typically lost 3–4 hours
after stopping IV infusion but potentially longer with large doses (e.g., after large
[>2,000 units] boluses, cardiac procedures, or subcutaneous administration).
•
Subcutaneous administration effects typically last 8–12 hours.
Pharmacologic effects rapidly reversed with protamine (see Table
Rebound anticoagulation effects from redistribution of UFH from
•
Monitoring by aPTT or anti-factor Xa activity with normal therapeutic dosing or
ACT when very high intensity dosing (e.g., catheterization lab, operating room).
Note: Return to baseline on high range ACT may still yield a venous thrombo
embolism (VTE) treatment target aPTT value.
ACT (low and high range) is used to measure higher levels of heparin
aPTT or anti-factor Xa activity level may be necessary to determine
Pharmacologic effects rapidly reversed with protamine (see Table
7
8-2).
tissues can occur after reversal with protamine when circulating
unfractionated heparin (UFH) persists, or after large doses used
during cardiopulmonary bypass.
related anticoagulation.
full reversal.
9-9).
11
-
PARENTERAL ANTI-FACTOR Xa ACTIVITY
ANTAGONISTS (LOW MOLECULAR WEIGHT
HEPARINS AND FONDAPARINUX)
Low Molecular Weight Heparins
•
Half-life of low molecular weight heparins (LMWHs) is 3–5 hours with effects
typically lasting 12–24 hours (may be longer in patients with renal impairment).
•
Value of anti-factor Xa activity monitoring in the setting of reversal has not been
established.
Note: 1 mg enoxaparin ~100 anti-factor Xa activity units
•
Protamine partially neutralizes LMWH, with only ~60% effective
Dosing (see Table 9-9)
•
Bleeding recalcitrant to protamine or imminent life-threatening bleeding, rFVIIa
(dose not established), or PCC can be considered. Low doses may be effective
to achieve goals and allow titration to effect as onset is rapid (minutes). Repeat
doses of protamine may need to be considered if activity is prolonged from
reduced elimination in renal insufficiency.
•
Andexanet alfa, an agent that can potentially neutralize LMWH, is available but
FDA approved only for reversing apixaban and rivaroxaban. No standard dosing
guidance is provided for LMWH reversal at this time.
2
ANTICOAGULATION REVERSAL: PART II 201
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TABLE 9-9: Protamine for Reversal of Heparins
Agent Dose Comment
Unfractionated
heparin
For IV heparin:
•
Protamine 1 mg/100 units
of heparin, maximum of
50 mg at rate not to
exceed 5 mg/min; if
>60 min after holding the
UFH infusion,
0.5 mg/100 units; if
>2 hr, 0.25 mg/100 units;
may give additional
after at least 10 min.
•
Higher doses of protamine
are used to reverse heparin
effects after high doses
during cardiopulmonary
bypass surgeries.
For subcutaneous heparin
•
(treatment dosing):
25–50 mg IV infusion
over 8–16 hr (with
bleeding/high risk of
bleeding: aPTT at goal,
use 25 mg; if elevated
aPTT, use 50 mg and
recheck aPTT)—see
Chapter 8.
Because the half-life of IV heparin is
relatively short (~60–90 min) with effects
dissipating rapidly after stopping the IV
infusion, consider calculating the dose
of protamine sulfate from the amount
of heparin administered within the
preceding few hours.
Can add the total amount of heparin
administered over the past 3 hours if no
recent bolus (> 8 hours past the bolus) as
the amount of heparin to neutralize.
After an IV UFH bolus and bleeding (or
high risk): 1 mg/100 units of UFH if aPTT
at goal; 1.5 mg/100 units of UFH if the
aPTT is elevated.
Infuse at 5 mg/min.
After large doses in cardiac bypass
graft surgery and initial protamine
reversal, redistribution of heparin out
of tissues to the plasma may lead to a
rebound heparin effect where additional
protamine may be considered when
bleeding concerns are present.
Neutralization of sub-Q UFH may require
a prolonged infusion of protamine sulfate
or repeat doses (e.g. in 4 hr depending
on how long it has been since the sub-Q
dose and how high the aPTT/anti-Xa
level is) until sufficient loss of effects.
7,12,17
11
LMWH • Protamine 1 mg/100 anti-
ACT: activated clotting time, aPTT: activated partial thromboplastin time, hr: hours, IV:
intravenous, sub-Q: subcutaneous, UFH: unfractionated heparin
factor Xa activity units IV
at 5 mg/min within 8 hr
of dose.
• If 8 hr or more after dose,
0.5 mg/100 anti-factor Xa
activity units.
• Consider repeat dose of
0.5 mg/100 anti-factor Xa
activity units if bleeding
continues.
The APTT/anti-Xa activity (or ACT) can
be used to assess the effectiveness of
protamine sulfate neutralization.
12
Tinzaparin >dalteparin >enoxaparin
(in order of effect) for neutralization by
protamine; any clinical significance of
this between agents is unknown.
12
Enoxaparin 1 mg ~100 anti-factor Xa
activity units.
202 Anticoagulation Therapy
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Fondaparinux
•
Long half-life (17–21 hours).
•
Monitoring of anti-factor Xa activity level requires a fondaparinux-specifically
calibrated anti-factor Xa assay value to determine if reversal is not established.
•
No definitive antidote data, but some limited short-term effect may exist with
rFVIIa and may be a consideration in life-threatening situations.
PCC (FEIBA™) hypothetically may have an effect (see PCC section below).
•
Protamine does not bind to fondaparinux and may not effectively reverse its
effects given the lack of sites on the molecule to elicit an effect, and similar
hypersensitivity precautions would still be a concern.
Concentrated Clotting Factors—LMWH/Fondaparinux
•
Prothrombin complex concentrates (PCC) may have a role in protamine recalcitrant reversal.
FEIBA: The ability of FEIBA to work downstream of anti-factor Xa activity in the
common pathway in the coagulation cascade has been postulated with limited
in vitro evidence as an advantage in reversing anticoagulation when in the
presence of an anti-factor Xa activity inhibitor (fondaparinux analyzed). Dose
of FEIBA proposed is 25 units/kg. However, lower doses may be effective to
achieve hemostatic target goals.
Note: PCC products contain clotting factors. FEIBA differs from other PCCs in
that some of the factors present are already in an activated form (Chapter 8). The
activated factors may produce immediate thrombin generation in the presence
of an anti-factor Xa activity inhibitor.
16
16
13-15
Activated
16
CONSIDERATIONS FOR DRUG
ADMINISTRATION
•
Protamine: Typically reserved for life-threatening bleeds during UFH or LMWH
therapy or to prevent risks of bleeding after very large UFH doses.
•
Chapter 8 contains information on the specific reversal agents.
•
Protamine can be administered undiluted in emergency situations, but dilution
in dextrose in 5% water (D5W) or normal saline (NS) is preferred.
DIRECT THROMBIN INHIBITORS
•
Parenteral DTIs used concomitantly with warfarin may elevate the INR value
above warfarin’s anticoagulation effects.
Elevated INR values secondary to DTIs in the absence of warfarin
may not reflect excessive loss of systemic vitamin K-dependent
clotting factors but a false positive influence on the assay; thus,
vitamin K should not be used for reversal if no warfarin has been
given.
The INR, aPTT, ecarin clotting time, or thrombin time may also be
elevated with oral DTIs. The INR’s ability to reflect a level of anticoagulant effect is unclear. As the DTI concentration rises, depend-
ANTICOAGULATION REVERSAL: PART II 203
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ing on the sensitivity of the assay, the INR can eventually rise.
Elevated INR values may actually suggest excessive anticoagulation
if no other causes are present (e.g., liver failure, DOACs).
If the prothrombin time (PT)/INR and aPTT are difficult to interpret
to assess loss of DTI effects, a thrombin time can be considered.
•
Prolonged effect due to reduced elimination in impaired cardiac, hepatic, or
renal function requires extended monitoring for recurrent bleeding or ongoing
bleeding risk.
•
In patients with normal organ function, the parenteral DTIs half-life is short
(~30–60 minutes depending on the product) and effects will minimize within
3–4 hours of stopping.
DTIs administered by the subcutaneous (sub-Q) or oral route may
have longer durations of actions.
A thrombin time may be a separate means to confirm decline of
anticoagulant effects.
Parenteral Direct Thrombin Inhibitors (Argatroban,
Bivalirudin)
Parenteral direct thrombin inhibitors in general have a relatively short halflife in healthy individuals. In the presence of organ failure, elimination may
be impaired and take a substantially longer time (>24 hours in selected
settings) to be removed. Little information is available on the reversal of the
parenteral DTI (Table 9-10).
•
Argatroban: No clear reversal agent or antidote is known. Elimination is hepatic,
but also reduced in renal failure (see Chapter 5). In severe organ failure, effects
may last several days.
•
Bivalirudin: No reliable data on reversal agents; however, low-dose rFVIIa has
been used along with ultrafiltration with some effect.
to verify this concept. Elimination is primarily enzymatic with some liver and
renal clearance. In hypothermia, elimination may be reduced.
•
Therapeutic responses on lower doses may suggest decreased elimination and
longer periods of time for the effects to decline (see Figure 9-2).
9,18
More data are needed
DIRECT-ACTING ORAL ANTICOAGULANTS
•
DTIs (dabigatran).
•
Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, betrixaban).
•
Shorter half-life in patients with normal organ function compared to warfarin
(range 5–37 hours depending on the product).
Effects may be prolonged in patients with renal, hepatic, or cardiac
•
Significant drug interactions with P-gp and/or CYP3A4.
dysfunction.
204 Anticoagulation Therapy
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TABLE 9-10: Considerations for Measuring and Reversing
Parenteral Direct Thrombin Inhibitors
Anticoagulant Examples
of Common
Laboratory Assays
to Consider
Reversal
Approach
Comment
Argatroban •
Bivalirudin •
ACT: activated clotting time, aPTT: activated partial thromboplastin time, rFVIIa: recombinant
activated factor VII
aPTT
•
ACT in
selected
cardiac
procedures.
Chromogenic
IIa and dilute
thrombin time
have been
explored
in limited
settings.
aPTT
• ACT in
selected
cardiac
procedures.
Hemofiltration
Effective means to reverse
argatroban have not been
established.
10
Limited evidence suggests
that rFVIIa (e.g., 1–2 mg) may
reverse effects.
the thrombin burst caused by
rFVIIa is creating the enzymatic
means to cleave apart and
inactivate bivalirudin. This
has not been explored or
validated under more rigorous
assessments. Based on case
observations.
19
Theory is that
•
Monitoring of anticoagulant effects (see Table 9-11).
PT/INR may not be elevated beyond the baseline values at thera-
aPTT may be more sensitive than the PT (INR) to dabigatran.
PT (INR) may be more sensitive than aPTT to anti-factor Xa agents.
peutic doses, and may be elevated with excessive serum concentrations from reduced elimination or overdose. Thrombin time (TT)
and ecarin clotting time (ECT using a ECA assay) are prolonged by
dabigatran only.
20,21
5,6,22,23
within a few hours, can consider low dose PCC or aPCC (approximately 8 units/kg) or tranexamic acid.
dosed between 8–25 units/kg and titrated to effect with the option for additional doses (up to ~50 units/
kg) total if hemostasis targets are not achieved and patient is still unstable or tranexamic acid at physician’s
discretion in traumatic non-ICH bleeding. Hemodialysis may be a secondary consideration in rare situations.
If very high dabigatran levels are present (>800–1000 ng/mL), additional idarucizumab may be necessary.
ranging for 8 units/kg to >50 units/kg. It is not clear what dose is necessary for optimal effect and may
depend on the timing for onset of the bleed and the location of the bleeding event (Appendix H). Doses <25
units/kg have been effectively used in single center case series with no apparent increased risk in thrombosis
bleeding management targets, the addition of aPCC at doses ranging from 8–25 units/kg or tranexamic acid
can be considered at the discretion of the treating physician. There are no supporting data on when or how
to combine a prohemostatic agent with idarucizumab with life-threatening bleeding events. Data are limited
will directly neutralize dabigatran, limiting the need for hemodialysis as a means to expedite
removal of drug. Onset of hemostasis may take several hours (in bleeding patients noting that time of data
can remove dabigatran depending on the amount present in the plasma. Drug levels have
been shown to rebound upon cessation of hemodialysis from tissue to plasma redistribution and rebound
rise in plasma levels; therefore, prolonged dialysis may be considered in selected situations (see
Can consider low-dose FEIBA™ (~8 units/kg) just prior to catheter placement for hemodialysis.
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ANTICOAGULATION REVERSAL: PART II 205
24
25
Comment
Pharmacologic
Reversal Agents
Laboratory
Anticoagulant Examples of
TABLE 9-11: Considerations for Measuring and Reversing Direct-Acting Oral Anticoagulants
• For minor bleeding: Monitor and re-check laboratory tests and assess bleeding.
• Semi-urgent major bleeding: Consider idarucizumab and if hemostasis desired in an active bleeding patient
• Urgent life-threatening bleeding: Idarucizumab 5-gm IV bolus with a consideration of adding a aPCC initial
• Idarucizumab
• aPCC or PCC
• Hemodialysis
Assays to
Consider
aPTT, INR, and,
if available,
dabigatran
level using ECA
or dTT assay
approaches
Dabigatran Thrombin time,
• In the setting of an ICH: aPCC doses of 25–50 units/kg have been suggested with reported experiences
INR may be
elevated
at high
concentrations
25,26
compared to FFP noted.
• In the setting of a major or life-threatening active bleeding: When idarucizumab alone may not achieve
relative to an effective approach for managing active bleeding.
Idarucizumab
•
collection may have influenced observations) for the cessation of bleeding.
Note: Dose to fully neutralize excessively high dabigatran levels not established.
•
Hemodialysis
•
206 Anticoagulation Therapy
Data on the agent and dose to reverse the effects of oral anti-factor Xa agents have not been established. Not
Some limited data have observed positive effects with low-dose aPCC (FEIBA™) 8–12 units/kg. If time
permits (non-ICH), can consider starting with a low dose and titrate to treatment goals. In the setting of an
ICH, the dose of PCCs is unclear. 25–50 units/kg are commonly recommended; however, use of lower doses
aPCC: activated prothrombin complex concentrates (FEIBA is a product example), aPTT: activated partial thromboplastin time, dTT: dilute thrombin time, ECA: ecarin
clotting assay, ICH: intracranial hemorrhage, INR: international normalized ratio, PCC: prothrombin complex concentrates
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Comment
Pharmacologic
Reversal Agents
Laboratory
Assays to
Consider
Anticoagulant Examples of
TABLE 9-11: (Continued)
23
has been reported.
Minor bleeding: Monitor any bleeding, re-check laboratory tests, and re-assess any need for a intervention.
dialyzable.
•
• Semi-urgent—major bleeding: Andexanet Alfa, PCC, or aPCC starting at low doses.
• Emergent life-threatening bleed: Andexanet Alfa, PCC, or aPCC—8–50 units/kg.
•
PCC or aPCC
Andexanet Alfa
aPTT,
chromogenic
anti-factor
Xa (consider
calibrating to
agent involved).
UHF and LMWH
calibrators can
be used, but
results may vary
Rivaroxaban,
apixaban,
edoxaban
ANTICOAGULATION REVERSAL: PART II 207
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• Hemostatic agents do not directly reverse DOACs,
but can drive hemostasis indirectly. The dose
has never been determined and may be situation
dependent. Because they create an independent
risk for thrombosis, the lowest effective dose may
be desirable. Given that the onset of effects from
these agents are rapid (in minutes), if semi-rapid
hemostasis is considered necessary, low doses can be
considered initially if time permits and titrated with
additional doses until target goals (prevention or
stabilization of bleeding) are achieved.
•
In the setting of intracranial hemorrhage (ICH), guidelines from the Neurocritical
Care Society recommend 50 units/kg of a PCC. Lower doses have been reported
in case reports or case series.
22
Overdose of DOAC: In the setting of an overdose, bleeding if not already
occurring may not happen until invasive procedures such as lines, etc., are
placed.
Dabigatran
•
Dabigatran half-life is longer than parenteral DTIs (12–17 hours).
•
In the presence of organ failure, effects of all DTIs may last longer after holding
secondary to slower elimination.
•
Dabigatran etexilate is approximately 80% renally cleared.
•
Idarucizumab: A U.S. Food and Drug Administration (FDA)-approved antidote
specifically designed to reverse dabigatran (see Chapter 8).
The recommended dose is a 5-gm IV bolus. Available in 2.5 gm in
50-cc vials with each vial infused over 5 minutes.
Idarucizumab reverses most concentrations of dabigatran for up to
24 hours in most patients.
A 5-gm dose may not fully reverse very high concentra-
tions. In such situations, a second dose may be necessary
for complete reversal of effects.
Onset of reversal is immediate.
Has no prothrombotic effects—It is unclear if additional adjunct
may be needed to stop active life-threatening bleeding.
In presence of bleeding and need for urgent reversal, data support-
ing preferred options between concentrated clotting factors or
tranexamic acid to establish hemostasis are unknown.
Hemodialysis can remove dabigatran (see Table 9-12).
Drug interactions with the oral agents may prolong their effects.
A TT may be a separate means to confirm decline of anticoagulant
effects.
24
23,27-30
208 Anticoagulation Therapy
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TABLE 9-12: Considerations for the Removal of Dabigatran by
Hemodialysis
Consideration Comment
Develop an approach in advance for
implementing emergent hemodialysis
for the removal of dabigatran.
Establish an approach to assessing
adequate drug removal. Determine
which assays will be used to measure the
removal of dabigatran.
Consider associated bleeding risks with
insertion of the dialysis catheter.
Initiate dialysis at a tolerable flow rate
(e.g., 400–500 mL/min). After a few
hours, the rate can be reduced to allow
removal of drug redistributing from
tissue compartments to the plasma. The
duration of dialysis may depend on the
amount of dabigatran in the system, the
patient’s ability to tolerate hemodialysis,
hemodialysis approach, blood flow rate,
and assay results confirming adequate
removal.
23,27-30
Limit any logistical delays or barriers to initiating
hemodialysis.
Coordination in advance if transferring the patient
to a higher level care facility.
Consider: TT, ECT, dilute TT. Declining values can
indicate removal of dabigatran; however, some
may be normal at therapeutic levels (aPTT, INR). A
normal TT may suggest sufficient removal.
Note: The use of more than one testing approach
may help confirm observations.
Low-dose aPCC (FEIBA) ~ 8 units/kg immediately
prior to insertion of the dialysis catheter has been
reported to be used safely.
In most case reports, a rebound in dabigatran
concentrations was observed after stopping
hemodialysis and notably less than two-thirds was
removed in the first 2 hr. Initial dialysis blood flow
rates of 200 mL/min removed 49% compared to
59% at 400 mL/min in one analysis of hemodialysis
for 4 hr. Initial dabigatran plasma concentrations
were approximately 159 ng/mL. Duration of
hemodialysis may be a strong predictor of overall
removal.
In one case report of a 9-gm overdose with a
dabigatran concentration of 1,560 ng/mL—CVVHF
x 32 hr successfully removed dabigatran—observed
extraction ratio was approximately 0.2.
aPTT: activated prothrombin thromboplastin time, CVVHF: continuous veno-veno hemofiltration,
dTT: dilute thrombin time, ECA: ecarin clotting assay, FEIBA: factor eight inhibitor bypassing
agent, INR: international normalized ratio, TT: thrombin time
•
Hemodialysis: Dabigatran pharmacokinetic studies exploring effects of hemodialysis used a single dose model and did not allow for tissue distribution and
over-estimated removal within the first 2 hours. Longer periods of hemodialysis
or even continuous renal replacement therapy may be necessary to remove
dabigatran depending on initial serum concentrations.
•
The TT is a very sensitive test for presence of DTI such as dabigatran. A normal
TT may suggest adequate loss of effect after holding or undergoing hemodialy
sis. Availability of idarucizumab should limit the need for hemodialysis as line
placement, etc., carries additional risks.
Anti-Factor Xa Antagonists—Potential Antidotes
•
The duration of oral anti-factor Xa antagonists’ effects can be days, especially in
the setting of organ failure with diminished elimination and potential accumula
tion to higher serum concentrations, or in the setting of an overdose.
-
-
ANTICOAGULATION REVERSAL: PART II 209
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•
Plasmapheresis has been successfully used in case reports (apixaban).
•
Additional antidotes are in development (see Chapter 8).
•
Initial studies currently available are primarily in non-urgent bleeding or
non-bleeding settings.
•
Measuring intensity of anticoagulation: It is unclear what laboratory approaches
can be used to determine the loss of anticoagulants effects sufficient enough
to stop the antidote.
•
Andexanet Alfa is available (see Chapter 8). Dosing and amount of reversal may
depend on the agent, time since the last dose, and level of anticoagulant effect
present if elimination impaired or in an excessively anticoagulated setting. For
use during surgical procedures with high bleeding risks, the andexanet alfa
infusion may need to be continued during the period of bleeding risk, which
could be longer than the 2 hours studied as the effects rapidly wear off after
stopping the infusion.
31
Clinical Consideration: In the setting of administering an antidote, the effects
of any anticoagulant neutralized will continue until the effects of the antidote
wears off. If the same class of neutralized anticoagulant (e.g., heparin) must
be emergently required (e.g., placing patient on extra corporeal life support
[ECLS]), it may be difficult to establish and measure the necessary level of
anticoagulation. If possible, delay the procedure until the effects of the
antidote wear off or consider an anticoagulant that is not neutralized (see
Tables 9-11 and 9-12).
• When using an antidote to reverse a DOAC, the
amount reversed will depend on the concentration
of drug in the plasma and tissues and the
amount of antidote administered (molar ratio).
High DOAC levels may not be fully reversed
with approved antidote doses. Higher antidote
doses may be necessary for full reversal. For
dabigatran, 800–1000 ng/mL is reversed by 5 gm
idarucizumab.
24
In the setting where complete
dabigatran reversal is desired with an initial
notably elevated INR prior to administration of
a 5 gm idarucizumab dose, a follow up thrombin
time may assist in determining any need for an
additional dose.
• For andexanet alfa, the dose studied in clinical
trials was agent dependent; however, patients
with excessively high levels of apixaban may
require a higher dose andexanet alfa for full
reversal.
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