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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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90 Anticoagulation Therapy
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TABLE 5-4: Considerations for Dosing DTIs in
Hemodialysis
Agent Consideration in Hemodialysis (see Table 15-3)
Argatroban •
Bivalirudin • When using bivalirudin for therapeutic use (not just to maintain the
a
Target aPTT may depend on the dialysis circuit and frequency of thrombosis-related
complications. An aPTT of 1.5–2 x baseline aPTT can be considered in place of heparin if
concurrently treating for HIT.
~: approximately, ACT: activated clotting time, aPTT: activated partial thromboplastin time, CRRT:
continuous renal replacement therapy, CVVH: continuous venovenous hemofiltration,
HD: hemodialysis, HIT: heparin-induced thrombocytopenia, sec: seconds, x: times
12,18,20-25
Unclear if dose adjustments are necessary as reports are not consistent.
•
For anticoagulation to maintain the circuit during intermittent HD only,
three regimens have been studied and found equivalent:
250 mcg/kg IV bolus at the start of hemodialysis with an additional
250 mcg/kg bolus allowed 2 hr later if ACT <140% of baseline
250 mcg/kg IV bolus followed by 2 mcg/kg/min
2 mcg/kg/min IV infusion started 4 hr prior to HD with target ACT
140–180 sec
CRRT: 100 mcg/kg IV bolus and 0.5 mcg/kg/min IV infusion. In the post-
•
cardiac surgery population using CVVH, a dose of 0.25 mcg/kg/min IV
infusion has been reported.
circuit), it is important to consider that some is dialyzed off, likely
necessitating an increase in the rate. The optimal management strategy
may depend on the duration of hemodialysis and aPTT value maintained,
along with the risk of thrombosis formation during HD. Consider aPTT
2 hr into HD to assess a need to temporarily increase the infusion rate
during prolonged dialysis (>8 hours).
Initial dose
• For treatment of HIT or antithrombin deficiency, consider the following:
Intermittent hemodialysis: 0.03–0.07 mg/kg/hr IV infusion
Extended duration hemodialysis: 0.06–0.09 mg/kg/hr IV infusion
CRRT: 0.06–0.07 mg/kg/hr IV infusion (range 0.03–0.1 mg/kg/hr)
As an alternative to heparin during intermittent dialysis only (no acute
•
thrombosis), start at ~0.03 mg/kg/hr. For CRRT: consider checking aPTT
and consider the lower end of the range (~1.5–2 x baseline).
Note: Based on total body weight and for infusing during and off
a
dialysis.
Note: Bivalirudin is removed during hemodialysis, so consider the following:
During intermittent or extended hemodialysis, avoid drawing aPTT
•
during or within 2 hours post-dialysis until the serum concentrations have
recovered.
• Administration of bivalirudin pre-filter in CVVH may decrease the
incidence of occlusion of the hemofilter.
• If CRRT is stopped, an aPTT should be considered and re-evaluation if the
bivalirudin dose needs to be lowered.
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Argatroban Dosing in HIT (See Chapter 18)
• Asians often need lower doses (1 mcg/kg/min).
Lower than doses observed in Hispanic or
African Americans.
26
• Critically ill patients often need lower doses
than package insert recommendations.
0.6 mcg/kg/min versus noncritical
1.4 mcg/kg/min.
Mean doses of 0.22 mcg/kg/min have been
reported.
8
7
• If weight >50% ideal body weight (IBW):
Initiate at 1 mcg/kg/min.
MONITORING (SEE TABLE 5-5)
TABLE 5-5: Target aPTT Range in the Setting of HIT
aPTT Range (Bivalirudin) Clinical Setting
Lower: 1.5–2 x baseline •
Higher: 2–2.5 x baseline •
AT: antithrombin, HIT: heparin-induced thrombocytopenia, HITTS: heparin-induced
thrombocytopenia thrombosis syndrome, x: times
Argatroban: 1.5–2.5 x baseline
Isolated HIT, AT deficiency or treatment of
•
thromboembolic complications when increased bleeding
concerns are present
Argatroban: 2–3 x baseline
HITTS and limited risk for bleeding
•
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Clinical Pearls in Managing and Monitoring DTI Regimens (See Tables 5-5,
5-6, and 5-7)
• Differences in sensitivities for aPTT reagents
between heparin or DTI may occur and, thus,
the target aPTT range for a DTI will not be the
same as heparin nor the same between different
DTIs. Furthermore, due to differences in aPTT
assays, the target range for a DTI will likely
vary between institutions.
Acutely ill patients such as those with renal,
•
hepatic, or cardiac dysfunction may reach target
aPTT values at a dose notably lower than
observed in the clinical trials.
•
Because most published dosing experiences are
based on aPTT monitoring, not serum DTI
concentrations, the actual dosing observed may
be different due to differences in aPTT assays.
• Bivalirudin dosing in acute coronary syndromes
(ACS): the target ACT in the Replace II ACS
trial was a bolus to maintain the ACT over
225 seconds. In subsequent ACS trials, ACT
monitoring of the bivalirudin was not required.
27
• Effects of bivalirudin on the ACT can be seen
within minutes of a bolus.
• Any DTI and no acute thrombosis and concerns
for bleeding present: Consider targeting aPTT
ratio of 1.5 to 2 x baseline (1.5−2.5 x baseline
argatroban) to minimize bleeding risks. Because
a higher incidence of thrombosis was seen in the
lepirudin trials, if half the aPTT values were
below 1.5 x control, lower targets may not be
preferred.
•
Although more consistent results have been
observed with alternative assays to monitor DTI
infusions compared to the aPTT, reductions in the
incidence of bleeding or thrombosis with their use
has not been established, and they were not used
in the clinical trials that led to market approval.
(continued)
PARENTERAL DIRECT THROMBIN INHIBITORS 93
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• Alterations in dosing requirements may be
necessary as the dynamic clinical presentation
of the patient changes. Measured aPTT values
should take this under consideration, and the
infusion rate should be adjusted to prevent
undershooting or overshooting target goals
Figures 5-1 and 5-2).
3
(see
94 Anticoagulation Therapy
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TABLE 5-6: Sample Adjustment Scale for a DTI
Agent _________________
Start infusion at ____________ (__________/hr)
Draw aPTT________ hr after starting infusion
Draw aPTT/INR/CBC every morning while on infusion
aPTT Rate adjustment
Rate adjustment Repeat aPTT Comment
by percentage
Less than
__________ sec
Increase infusion
rate by 40%
Increase infusion
rate
__________
________ to
_________ sec
Increase infusion
rate by 20%
Increase infusion
rate
_____________
Goal aPTT
No change No change Draw aPTT/INR
___________
____________
to
__________ sec
Greater than
__________ sec
Decrease infusion
rate by 20%
Decrease infusion
rate by 40%
Hold for 1–2 hr
b
Decrease
infusion
rate _________
Decrease
infusion
rate __________
Hold for 1–2 hr
Baseline aPTT ________________
Baseline INR _________________
Call physician if the rate exceeds
_________________________
4–6 hr
4–6 hr
4–6 hr
4–6 hr
b
a
every morning
b
For low infusion
rates (defined
based on agent)
and aPTT >100
sec (could vary
based on hospital
reagent), hold 2
hr; if at a higher
rate (defined
based on agent),
hold 1 hr
Clinical thrombosis: Target 2–2.5 x baseline for bivalirudin (2–3 x baseline argatroban).
No apparent clinical thrombosis: Target aPTT 1.5–2/2.5 x baseline.
Rate adjustment units (mg/hr, mcg/kg/min, mg/kg/hr) can vary between institutions and the
agent used.
For argatroban: When using argatroban, adjust initial dose in the following fashion
Asian: 1 mcg/kg/min
•
• Hepatic impairment (Child-Pugh >6): 0.5 mcg/kg/min
• Critically ill: 0.6–1 mcg/kg/min
• Critically ill with multisystem organ impairment: 0.2–0.5 mcg/kg/min
• See Table 18-14
a
aPTT target determined by agent, baseline value, and presence of thrombosis.
b
Use dry weight for calculations in anasarca.
aPTT: activated partial thromboplastin time, CBC: complete blood count, hr: hours, INR:
international normalized ratio, sec: seconds
b
:
PARENTERAL DIRECT THROMBIN INHIBITORS 95
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TABLE 5-7: Monitoring Considerations When Initiating and
Adjusting a DTI Regimen
Initiating DTI
•
Draw baseline aPTT and INR if not previously done; if a true baseline aPTT is not possible,
use laboratory normals to help set targets.
Evaluate renal, liver, and cardiac function for potential reasons to reduce the dose.
•
•
Initiate DTI depending on target goals and indication for use.
Monitoring DTI (see Figures 5-1 and 5-2)
Draw aPTT at a predetermined time within 2–6 hr to reduce the risk of overtargeting or
•
undertargeting the selected aPTT goal. Note that the initial value reported may not be at
steady-state in acutely ill patients.
• Adjust dose upward any aPTT value notably below a ratio of 1.5 X baseline.
•
Consider adjusting the dose downward if the upper end of the target range is noted
shortly after initiating the infusion, or above prior to achieving steady state.
Follow thrombosis progression, platelet count (HIT), patient, and HCT (or hemoglobin) for
•
any evidence of bleeding.
If an INR was drawn before starting warfarin while on the DTI, consider an aPTT with it to
•
determine amount of DTI effect on the INR.
•
A flattening of the aPTT dose response curve has been observed at higher degrees
of anticoagulation intensity with minimal change in the aPTT as the DTI concentration
increases (see Chapter 21).
• The ACT has been used in situations where a higher degree of anticoagulation may
be required, such as invasive cardiac or selected surgical procedures (e.g., coronary
intervention, cardiopulmonary bypass, or ECLS).
• The DTI can independently elevate the INR value by interfering with the assay in the
laboratory. Absent of warfarin, this should not be interpreted as an elevated degree of
anticoagulation. The degree of effect on the INR often correlates with the concentration
of the DTI present, which is also represented by the intensity of rise in the aPTT. At higher
doses, a more pronounced elevation in the INR for any DTI can occur. Argatroban generally
leads to the largest INR elevations followed by bivalirudin and then lepirudin, which has the
least effect on INR. Stopping DTI therapy after seeing an INR over 2 without considering
the effect of DTI on INR is a very common clinical error that needs to be prevented.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, DTI: direct
thrombin inhibitor, ECLS: extracorporeal life support, HCT: hematocrit, HIT: heparin-induced
thrombocytopenia, INR: international normalized ratio, x: times
96 Anticoagulation Therapy
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Low Clearance
2.5–3 X contro
Moderate Clearance
1.5 X control
High Clearance
aPTT
FIGURE 5-1. Considerations for Measuring aPTT Values at the
Initiation of a DTI Infusion
The initial aPTT may depend on plasma clearance. An early aPTT in the upper end of the
target range might signal a reduced ability to eliminate the DTI.
aPTT
Ratio
2.5–3 X contro
FIGURE 5-2. Optional Approach to Titrating DTI Infusion into
the Target Range in the Presence of Notable Bleeding Concerns
The dotted line represents potential aPTT values above the target in the setting of
reduced DTI elimination that is not recognized early in the course of therapy. The
solid line describes a strategy of starting a lower infusion rate and titrating upward to
minimize risk of overshooting the target when notable bleeding concerns are present.
Source: Adapted from Dager WE. Considerations for drug dosing post coronary artery
bypass graft surgery. Ann Pharmacother. 2008;42:421-424. Copyright© 2008. Reprinted
by permission of SAGE Publications.
1.5 X control
time
Dose ↑ Dose ↑
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• Due to the potential flattening of the aPTT at
high concentrations of DTI, following the INR
in conjunction with the aPTT can be considered
when very high doses of DTI are given. You may
be experiencing this flattening of the aPTT doseresponse curve if the aPTT is not rising with
increasing DTI doses but the INR is continuing
to increase. In this situation, since the serum
level of the DTI is likely still rising, the INR and
thrombin time (TT) may now be a guide for
assessing dosing titrations.
• In situations of confirmed HIT and lack of
platelet response, consider reassessing target
aPTT values and dosing titration scale.
Transitioning from a DTI to
warfarin
3,12,16,17,20-22,27-33
Note: aPTT and INR responses to a DTI and
warfarin separately vary between assays (see Table
5-8).
• Draw a baseline INR and aPTT on DTI
therapy alone.
• Initiate warfarin and identify a desired
1.5–2 point increase in the INR or pick a
preselected INR, which considers the DTIinduced INR prolongation (with minimal
change in the aPTT).
Once the desired number of overlap days and
•
desired platelet recovery has occurred and
the INR target is reached, hold the DTI for
4–8 hours and recheck the INR and aPTT.
• After withholding the DTI and the subsequent
INR is over 2 with an aPTT close to baseline
(indicating the DTI has largely cleared), then
the DTI can be discontinued. It may take
longer for the effects of a DTI to diminish if
a very low infusion rate has been used and
aPTT values are in the target range, as this
suggests slower drug elimination (Figure 9-2).
(continued)
98 Anticoagulation Therapy
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•
Another option may be the use of
Note: Slight differences in the percent range can occur
between assay methods.
If the INR is less than 2 or in the lower portion
of the INR range with a continued notable
elevation in the aPTT, restarting the DTI
infusion may be necessary.
chromogenic factor X (not anti-Xa activity)
or factor II to assess if an adequate
anticoagulation response with warfarin has
occurred.
30-32
Factor X <11% = INR >3.5
Factor X of 11% to 42% ~INR 2–3.5
Factor X >42% = INR <2
Factor II targets of 20% to 35% ~INR 2–3
SPECIAL POPULATIONS
TABLE 5-8: Influence of Direct Thrombin Inhibitors on Selected
Assays
No effect: D-dimer; Von Willebrand’s factor; chromogenic plasminogen, antithrombin (slight
elevation observed).
dRVVT: dilute Russel viper venom test (test for present of lupus anticoagulant)
31
Agent Effect
•
Argatroban
Bivalirudin
Increased protein C and protein S
Increased dRVVT
•
• Decrease fibrinogen, factor II, and factor
• Increased protein C and protein S
• False positive lupus anticoagulant ratios
• Decreased factor IX
IX
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Coronary Artery Bypass Grafting and Procedures
Requiring Cardiopulmonary Bypass
•
HIT is rare with the exception of recent exposure to heparin.
•
Heparin is the anticoagulant of choice in coronary artery bypass grafting (CABG)
with a pump unless patient has reasons not to use.
•
Suggested management options if patient requires CABG when heparin contraindicated:
Delay procedure until heparin antibody cannot be detected (several
months).
Use alternative anticoagulant.
•
Suggested alternative anticoagulant dosing during CABG under HIT conditions:
DTI infusion rates post-open heart surgery may be lower than in the
pre-operative setting as organ function and, thus, elimination may
be diminished. Platelet count most likely will drop after surgery.
• Because bivalirudin can be cleaved and
inactivated by thrombin in stagnant blood,
blood clotting in small pockets outside the
circulation within the surgical field—unlike
with heparin—does not suggest insufficient
anticoagulation.
Mechanical Circulatory Devices
36,37
Heparin is commonly used in the setting of mechanical circulatory support
to sustain blood flow and prevent clotting of the circuit (see Chapter 17).
Some components of using DTIs in this setting are discussed in Chapter 17.
In situations where heparin is not an option and an alternative short-acting
anticoagulant is required, parenteral DTIs may be considered. Dosing and
goals of therapy will depend on the need for either sustaining the circuit or
independent. systematic anticoagulation of the patient.
Goals of Therapy
•
May be different for sustaining the circuit, and monitoring may be based on
assessment of clotting within the circuit (e.g., extracorporeal life support [ECLS]),
function of the device (e.g., ventricular assist devices).
•
Laboratory assessment of the DTI should still occur to make sure excessive
anticoagulation effects and potential complications such as systemic bleeding
are identified.
•
It is unclear what the target goals are and which test (aPTT or ACT) should be
used because information is limited based on single-center case reports or small
case series (if any information at all).
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