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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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70 Anticoagulation Therapy
https://t.me/med1917
• Initiation of therapy for acute indications should
Administration times should be scheduled to
•
•
Clinicians should be aware that fluctuations in
LMWHs and fondaparinux are available in
•
•
be prompt.
reduce potential for missed or late doses.
weight may require dose adjustment.
color-coded, prefilled, and graduated and
non-graduated syringes. Rounding the dose to
a convenient syringe size may be considered.
Doses available in graduated syringes should be
rounded only to the nearest 0.1 mL. See Table
4-4 for commercially available syringe and vial
sizes.
When rounding to the nearest syringe size, clinically
significant changes in dose can occur when
rounding in low-weight individuals (<50 kg).
For
example, rounding down to a 40 mg syringe of
enoxaparin in a 45 kg patient
represents an 11%
dose reduction as compared to rounding down
to an 80 mg syringe in an 85 kg patient, which
represents only a 6% dose reduction.
Administration
•
For subcutaneous administration, patients may self-inject only if their physicians
determine that it is appropriate and with medical follow-up, as necessary. Proper
training in subcutaneous injection technique should be provided (see Patient
Education section).
•
Subcutaneous administration should be alternated between the left and right
anterolateral and left and right posterolateral abdominal wall.
•
For intravenous enoxaparin injection, the multiple-dose vial should be used.
When administered intravenously, enoxaparin should not be mixed or co-admin
istered with other medications.
-
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 71
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TABLE 4-4: Commercially Available Strengths/Formulations of
LMWH and Fondaparinux in the United States
Enoxaparin Dalteparin Fondaparinux
Dose/
Concentration
30 mg/0.3 mL Medium
40 mg/0.4 mL Yellow 5,000
60 mg/0.6 mL
80 mg/0.8 mL
100 mg/1 mL
120 mg/0.8 mL
150 mg/1 mL
300 mg/3 mL
multidose vial
a
Graduated prefilled syringes.
units: International Units
Packaging
Color
Blue
a
Orange 7,500
a
Brown 10,000 units/
a
Black 12,500
a
Purple 15,000
a
Navy Blue 18,000
Red 95,000
Dose/
Concentration
2,500
units/0.2 mL
units/0.2 mL
units/0.3 mL
1 mL
units/0.5 mL
units/0.6 mL
units/0.72 mL
units/3.8 mL
Packaging
Color
Blue 2.5 mg/0.5 mL Blue
Orange 5.0 mg/0.4 mL Orange
Green 7.5 mg/0.6 mL Pink
a
Peach 10 mg/0.8 mL Purple
Gray
Purple
Yellow
Teal
Dose/
Concentration
Packaging
Color
COMMON SIDE EFFECTS, PRECAUTIONS,
AND CONTRAINDICATIONS
The most common side effect associated with LMWH and fondaparinux
is minor and major bleeding. Minor bleeding events, such as ecchymosis
and epistaxis, occur more frequently than major bleeds such as hematuria,
hematomas, and hemorrhages. Major bleeding event rates are dependent
on the medical indication and intensity of anticoagulation. UFH is associated with major bleeding rates of 5–10% when used for the prophylaxis
or treatment of venous thromboembolism. Comparatively, major bleeding
rates are 2–4% with enoxaparin and fondaparinux. Management of bleeding
may include temporary discontinuation of the medication to reversal with
protamine and clotting factor concentrates. Non-bleeding adverse effects
occur infrequently, including thrombocytopenia and hyperkalemia. Table 4-5
summarizes and compares the possible contraindications and side effects of
the LMWHs and fondaparinux.
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72 Anticoagulation Therapy
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TABLE 4-5: Side Effects, Precautions, and Contraindications of
LMWH and Fondaparinux
LMWH Fondaparinux
Contraindications/
Precautions
•
Hypersensitivity
Active major
•
bleeding
Thrombo-
•
cytopenia
associated with
a positive in
vitro test for
antiplatelet
antibody in the
presence of
LMWH
• History of
or current
heparin-induced
thrombocytope
nia (HIT)
• Neuraxial
anesthesia
a
See Thrombocytopenia section for additional information.
b
See Neuraxial Procedures section for additional information.
c
Guiding-catheter thrombosis has occurred when fondaparinux was used as the sole anticoagulant
during percutaneous coronary intervention (PCI); therefore, an adjunct anticoagulant with
antithrombin activity (e.g., UFH) is recommended during PCI. It must take into account whether
glycoprotein IIb/IIIa antagonists have been administered. Use of fondaparinux during primary PCI
is not recommended.
CrCl: creatinine clearance, LMWH: low molecular weight heparin
Side Effects Contraindications/
•
Bleeding
Thrombo-
•
cytopenia
• Spinal and
epidural
hematomas
• Hyperkalemia
(suppression
of aldosterone
production)
-
a
Precautions
• Hypersensitivity
•
Active major
Thrombocyto
•
b
Neuraxial
•
•
Bacterial
CrCl <30 mL/
•
Body weight
•
•
Catheter tip
bleeding
penia associated
with a positive
in vitro test for
antiplatelet
antibody in the
presence of
fondaparinux
anesthesia
endocarditis
min
<50 kg (prophy
laxis)
thrombosis
-
-
c
Side Effects
• Bleeding
Thrombo-
•
cytopenia
• Spinal and
epidural
hematomas
a
b
Thrombocytopenia
•
Cases of LMWH-induced thrombocytopenia and thrombosis (similar to heparininduced thrombocytopenia [HIT]) have been observed. Use is not recommended
in patients with current HIT due to high cross-reactivity to heparin-platelet
factor-4 antibody. Avoid in patients with history of HIT, especially if administered
within 100 days of HIT episode because heparin-platelet factor-4 antibodies
may still be present.
•
Rare cases of thrombocytopenia with thrombosis similar to HIT have also been
reported with fondaparinux administration; however, fondaparinux use has
also been reported in patients with current or history of HIT due to a lack of an
immune-mediated effect on platelets.
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 73
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•
Discontinue therapy and consider alternative treatment if platelets are <100,000/
3
mm
, platelets decrease 50% from baseline, and/or thrombosis develops.
Reversal
•
Protamine sulfate can be used as a partial reversal agent for the effects of LMWH
(neutralizes approximately 60% of the anti-Factor Xa activity). Refer to
4-6 for recommended dosing of protamine.
•
There is no specific antidote for reversal of fondaparinux.
TABLE 4-6: Dosing of Protamine for the Reversal of LMWH
Timing of LMWH Dose Protamine Dose
Last dose given in previous 8 hours 1 mg of protamine for every 1 mg (100 units) LMWH
a
Table
Last dose given in previous 8–12 hours 0.5 mg of protamine for every 1 mg (100 units)
Last dose given more than 12 hours ago Use of protamine is not recommended
a
Repeated doses of protamine 0.5 mg for every 1 mg (100 units) LMWH may be considered if
anti-Xa level remains elevated or if bleeding continues.
LMWH: low molecular weight heparin, units: International Units
LMWH
RECOMMENDATIONS FOR TIMING IN
PATIENTS UNDERGOING NEURAXIAL
PROCEDURES
The use of anticoagulants in patients undergoing neuraxial anesthesia or
spinal puncture poses a significant risk for epidural and spinal hematoma.
Bleeding complications involving the spine can result in long-term or permanent paralysis. The time since the previous dose and/or next dose relative
to the catheter placement or spinal puncture should be carefully considered
(Table 4-7).
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74 Anticoagulation Therapy
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TABLE 4-7: Considerations of Use of LMWH or Fondaparinux
Administration with Neuraxial Procedures
Anticoagulant Minimum
Therapeutic or
prophylactic doses
of fondaparinux
Therapeutic
doses of LMWH
(enoxaparin or
dalteparin)
Prophylactic
doses of LMWH
(enoxaparin or
dalteparin)
a
See Chapter 10, Table 10-7.
b
Longer elimination times will be required in patients with impaired renal function.
LMWH: low molecular weight heparin
Time Between
Anticoagulant
Dose and
Insertion of
Spinal Needle
or Placement
of Epidural
b
Catheter
36–48 hr Avoid while
24 hr
10–12 hr
Minimum
Time Between
Insertion of
Spinal Needle
or Placement
of Epidural
Catheter and
Anticoagulant
Dose
catheter is in
place.
a
Minimum
Time Between
Anticoagulant
Dose and
Removal of
the Epidural
Catheter
Ideally avoid
while catheter is
in place.
If considered,
then just before
the next dose
and when
anticoagulant
effect is at
minimum.
Minimum
Time Between
Removal of
the Epidural
Catheter and
Anticoagulant
Dose
(provided
hemostasis has
been achieved)
2 hr
MONITORING
•
LMWHs and fondaparinux have a predictable anticoagulant dose response and
wide therapeutic windows; thus, routine dosage adjustments and monitoring of
anticoagulation activity are not required in the majority of patients.
•
The prothrombin time/international normalized ratio (PT/INR), activated partial
prothrombplastin time (aPTT), and activated clotting time (ACT) are inappro
priate laboratory markers to monitor the anticoagulant effect, as they are only
minimally affected by LMWHs and fondaparinux.
•
LMWHs have minimal effect on Factor IIa; thus, limited prolongation of aPTT
may be seen in cases of LMWH overdoses.
•
Refer to Table 4-8 for specific monitoring parameters and laboratory draw times.
1,4,7-10,14-15
-
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 75
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TABLE 4-8: Monitoring Parameters for LMWH and
Fondaparinux
Baseline (prior to initiation of therapy) Ongoing (every 3–4 days in inpatient setting)
CBC (specifically hemoglobin and platelets)
Serum creatinine
Creatinine clearance
CBC (specifically hemoglobin and platelets)
Serum creatinine
Creatinine clearance
Role of Anti-Factor Xa Monitoring (see Chapter 21)
•
This is not routinely recommended due to lack of clinical outcomes data.
•
This may be useful and considered in certain high-risk situations such as the
following:
Morbid obesity (weight >190 kg or body mass index >40 kg/m
(see Chapter 11)
Very low body weight (weight <50 kg)
Significant renal impairment (CrCl <30 mL/min) (see Chapter 11)
Neonates and pediatric patients (see Chapter 20)
Pregnant women (see Chapter 19)
Patients who receive extended therapy (>1 month)
•
When measuring anti-Factor Xa peak activity, the sample should be obtained
after steady-state concentrations of the LMWH or fondaparinux are attained,
usually after the third to fourth dose. Refer to Table 4-9 for a sample LMWH
dosing nomogram using anti-Factor Xa peak levels.
•
The anti-Factor Xa activity assay for fondaparinux has to be specifically calibrated
for fondaparinux, and many laboratories do not offer this option.
•
Anti-Factor Xa activity levels should be collected during peak drug concentrations (typically occur approximately 4 hours after a subcutaneous dose). Refer
to Table 4-10 for indication-specific goals for anti-Factor Xa peak levels.
•
Trough anti-factor Xa activity levels may be useful to rule out drug accumulation,
such as in patients with renal failure, and are typically measured just prior to the
next dose of the LMWH or fondaparinux.
2
)
76 Anticoagulation Therapy
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TABLE 4-9: Sample LMWH Twice-Daily Dosing Nomogram
Based on Peak Anti-Factor Xa Activity for VTE Treatment
Peak Anti-Factor Xa
Activity Level
<0.35 units/mL Increase dose by 25% 4 hr after next dose
0.35–0.49 units/mL Increase dose by 10% 4 hr after next dose
Dose Modification When to Repeat Anti-Factor Xa
Activity Level
0.5–1 units/mL No dose adjustment needed Next day, then in 1 week, then
1.1–1.5 units/mL Decrease dose by 20% Before next dose
1.6–2 units/mL Hold 3 hr, then decrease dose
by 30%
>2 units/mL Hold until level <0.5 units/mL,
then decrease dose by 40%
LMWH: low molecular weight heparin, VTE: venous thromboembolism
Source: Adapted from Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in
children. Chest. 2001;119 (suppl 1):344S–370S. Used with permission from Elsevier ©2001.
monthly
Before next dose and 4 hr after next
dose
Before next dose and q12 hr until
level <0.5 units/mL
TABLE 4-10: Goal Anti-Factor Xa Activity Levels Based on
Indication
Indication Goal Anti-Factor Xa Level (peak)
• Prevention of VTE • 0.2–0.4 units/mL
• Treatment of VTE • 0.6–1 units/mL
a
Goal peak levels are assuming twice daily dosing. For once daily dosing, higher goal peak levels
of 1–2 units/mL have been suggested, but data are limited.
VTE: venous thromboembolism
a
PATIENT EDUCATION
•
Patients should be provided with written and verbal instructions prior to receiving LMWH or fondaparinux as an outpatient.
•
Some institutions provide patient education kits that contain demonstration
syringes, supplies, and instructions for patient education prior to use in the
outpatient setting.
Patients should be informed of the following:
•
The site of administration should be rotated.
•
Squirting out of the air bubble in syringes can lead to more bruising at the injection site and/or not all of the dose being administered. Priming the needle is
not recommended prior to injection.
•
It may take longer than usual to stop bleeding.
7-9
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 77
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•
Bruising and/or bleeding may occur more easily.
•
Unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark
red spots under the skin) should be reported to their physician immediately.
•
Their physicians and dentists should be made aware that they are taking LMWH
or fondaparinux.
•
Other medications, including some over-the-counter medications, may increase
the risk of bleeding and/or bruising (e.g., antiplatelets, NSAIDs).
•
Refer to Table 4-11 for a list of steps in the self-administration of LMWH and/
or fondaparinux.
TABLE 4-11: Steps for Self-Injection of LMWH or Fondaparinux
Step Instruction
1 Wash and dry hands thoroughly.
2 Sit or lie in a comfortable position, so that you can see your abdomen.
3 Choose an area on the right or left side of your abdomen, at least 2 inches from your
4 Clean the injection site with an alcohol swab, and let air dry.
5 Remove the needle cap by pulling it straight off the syringe and discard it in a sharps
6 Hold the syringe like a pencil in your writing hand.
7 With your other hand, pinch an inch of the cleansed area to make a fold in the skin.
8 Press the plunger with your thumb until the syringe is empty.
9 Pull the needle straight out at the same angle that it was inserted and release the skin
10 Carefully activate the needle’s safety shield.
11 Place the used syringe in a sharps collector.
a
Some manufacturer discharge kits are equipped with a sharps collector. If one is not provided, it
may be purchased or patients can be educated to use any hard, plastic container (e.g., milk jug,
laundry detergent container).
b
If a dose adjustment is necessary, carefully discharge solution to the desired dose before
administration.
LMWH: low molecular weight heparin
belly button or scars.
a
collector.
b
Insert the full length of the needle straight down—at a 90º angle—into the fold of
skin.
fold.
a
78 Anticoagulation Therapy
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SPECIAL POPULATIONS
4,13,16
Pregnancy and Pediatrics
The pharmacokinetics of LMWH and fondaparinux vary in pregnant women
and pediatric patients. Adjustments to dosing regimens may be necessary in
these patients due to differences in the volume of distribution, metabolism,
and clearance. Therefore, therapeutic drug monitoring is recommended in
these special populations more frequently than the general patient population.
Dosing and monitoring of LMWH and fondaparinux in pregnancy and
pediatric patients will be covered in Chapters 19 and 20, respectively.
Morbid Obesity Dosing Considerations for VTE
Due to a larger volume of distribution in patients who are morbidly obese,
adjustments to dosing regimens may be necessary. The definition of morbidly
obese may vary from one institution to another and may be based on body
weight or body mass index. Additionally, therapeutic drug monitoring is
recommended more frequently in obese patients than the general patient
population. Dosing and monitoring of LMWH and fondaparinux in obese
patients will be covered in Chapter 11.
• Total body weight appears to be a good predictor
for dosing of LMWHs and fondaparinux in obese
patients.
• Setting a maximum dose (dose capping) is not
recommended when treating patients for VTE.
This practice may result in underdosing, putting
patients at risk for thrombotic complications.
•
Fondaparinux 10 mg sub-Q daily is approved
for VTE treatment in patients weighing >100
kg. There are not sufficient data to support
dose adjustments in obese patients for VTE
prophylaxis.
When using LMWHs for VTE prophylaxis, a
•
25–30% dose increase or weight-based dosing of
50 units/kg/day may be considered.
• For enoxaparin, the 1.5 mg/kg sub-Q daily
dosing strategy should be avoided in obese
patients with VTE.
(continued)
LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 79
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• In all obese patients, consider anti-Factor
Xa monitoring to assess dosing of LMWH or
fondaparinux. See Monitoring section for more
information.
Dosing Considerations in Underweight Patients
•
For VTE prophylaxis, fondaparinux is contraindicated in patients weighing <50 kg.
•
For VTE treatment, fondaparinux 5 mg sub-Q daily is recommended for patients
weighing <50 kg.
•
Fixed prophylactic doses of LMWH or fondaparinux in underweight patients (<50 kg)
may result in drug accumulation and increased risk of bleeding complications.
Consider anti-Factor Xa monitoring to assess dosing of LMWH and fondaparinux
in this patient population. Also see Monitoring section for more information.
Dosing Considerations in Renal Dysfunction
Because LMWHs and fondaparinux are renally eliminated, reduced elimination can result in increased drug concentrations and an increased bleeding
risk. The actual degree of accumulation is different for the various LMWHs
and fondaparinux as there are differences in their pharmacologic profiles.
Refer to Table 4-12 for a description in how these pharmacokinetic changes
impact the dosing and monitoring. Additional considerations in renal impairment are discussed in Chapter 11.
Considerations in Oncology Patients
Special LMWH dosing should be considered in patients with malignancy.
These agents may be preferred for chronic management due to their inhibition of tissue factor pathway inhibitor. Although malignancy increases the
risk for thrombosis, bleeding risk may also be increased in these patients
with special attention placed on platelet count. For dosing and monitoring
of LMWH and fondaparinux in oncology patients, see Chapter 11.
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