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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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260 Anticoagulation Therapy
https://t.me/med1917
TABLE 11-7: Dosing Considerations to Prevent Thrombosis of
the Hemodialysis Circuit
Agent Intermittent Hemodialysis Continuous Renal
Heparin See Chapter 3 See Chapter 3
Dalteparin 5,000 units IV or 39 units/kg have
been explored. Dose is given prior to
hemodialysis.
95 units/kg of dalteparin via the arterial
line just prior to starting of 8 hr nocturnal
hemodialysis followed by a dose of 45
units/kg at 4 hr was able to prevent
circuit thrombosis. Measured anti-factor
Xa activity was 0.34 at 4 hours and 0.49
at the end of an 8-hr dialysis session.
Dalteparin given either 5,000 units IV or
≥7,000 units with an additional ≥1,000
units at 2 hr in a ~ 4-hr dialysis yielded
end of dialysis anti-factor Xa levels of
0.15 and 0.6, respectfully. No difference
in clot formation was noted in the
dialyzer or air trap.
Dalteparin 60 units/kg (~5,000 units
arterial side) was safe and effective in
preventing circuit thrombosis in high-flux
HD and HDF. Measured anti-factor Xa
levels at 1 hr were 0.4–0.75 IU/mL and
<0.4 IU/mL (mean 0.26) at the end of the
session.
Dalteparin 7,500 units yielded the same
end of dialysis anti-factor Xa activity. No
accumulation was noted, and assessment
was done after dosing for 10 dialysis
sessions. The regimen was still indicating
success in 53 of the 55 patients at 4
months.
33-43
Replacement
40-43
CVVHDF:
33
Dalteparin 20 units/kg vs.
10 units/kg/hr vs. UFH: No
difference in filter life
CVVH:
Dalteparin 70 units/kg;
30–40 units/kg/hr vs. UFH: No
differences in filter life (~31 hr)
34
35
36
Enoxaparin 0.4–0.8 mg/kg appears to be effective
in protecting the dialysis circuit. Higher
doses may be considered if prolonged
duration of dialysis.
37-39
High-flux dialyzers (larger pore sizes) may
be associated with increased removal
and lower measured anti-factor Xa
activity.
CVVHDF:
Enoxaparin sieving coefficient
0.31–0.67
(continued)
a
:
TABLE 11-7: (Continued)
https://t.me/med1917
CONSIDERATIONS IN SPECIAL POPULATIONS 261
Agent Intermittent Hemodialysis Continuous Renal
In one prospective, randomized, crossover trial (n=36), pre-dialysis enoxaparin
1 mg/kg vs. UFH 5,000 units resulted
in increased minor bleeding with
enoxaparin. Reducing the enoxaparin
dose to 0.69 mg/kg resulted in a 44%
reduction in minor bleeding.
Thrombosis rates: 0.5% UFH vs. 0.1%
enoxaparin after adjusting the dose.
Minor bleeding: Enoxaparin 4.3% vs.
UFH: 2.8% (p<0.001).
a
Sieving coefficient is calculated by dividing the concentration in the ultrafiltrate by the plasma
concentration.
HD: hemodialysis, HDF: high-flux dialysis, CVVH: continuous venovenous hemofiltration, CVVHD:
continuous venovenous hemodialysis, CVVHDF: continuous venovenous hemodiafiltration, UFH:
unfractionated heparin
Replacement
CVVHDF:
Enoxaparin 0.5 vs. 1 mg/kg/day
vs. UFH: No difference in filter
life (~24 hr)
CVVHD:
Enoxaparin ~3.5–4.4 mg/hr
(86 mg/day): Anti-Xa ~0.3
units/mL
Filter life 31 hr vs. 22 hr (UFH)
40-43
Caveats for Consideration
•
Based primarily on small studies and experience. Anti-Xa activity of ~0.2 to
0.4 units/mL has been proposed as a target goal to prevent thrombosis of the
circuit. Lower level at the end of dialysis, however, has been observed in effec
tive therapies. If a patient is receiving systemic anticoagulation with a parenteral
agent, additional parenteral anticoagulation for protection of the circuit may
not be necessary.
•
The technology of the dialysis circuits and filters continues to evolve and may
impact observed outcomes. In general, as more efficient dialyzers are used,
elimination may increase.
•
More convective approaches of hemodialysis may be associated with a higher
rate of thrombosis.
•
In the setting of hemodialysis and requirement for systemic anticoagulation,
heparin (typically by continuous infusion) and warfarin are the established
therapies.
One option explored in a single center study, matched for indication
compared adjusted dose heparin to enoxaparin 0.7 ± 0.2 mg/kg/
day (range 0.1–1 mg/kg/day) for 3.3 ± 4.2 doses while transition
ing to warfarin. Enoxaparin was associated with a lower rate of
major bleeding (6.1% vs. 11%; p = 0.04), clinical thrombosis (0%
vs. 2.4%; p=0.5), and duration of hospital stay (20 ± 54 days vs.
29 ± 44 days; p = 0.02). This suggests that enoxaparin doses of
-
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262 Anticoagulation Therapy
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around 0.6–0.7 units/kg may be a feasible option to bridge when
continuous infusion heparin is not an option or able to transition
to warfarin as an outpatient.
• Laboratory monitoring of LMWH has
been proposed in patients with severe renal
impairment and those with moderate renal
impairment and prolonged use (>10 days) to
identify potential accumulation and need for
dose adjustment to prevent bleeding. However, no
guide or data exist on outcomes of thrombosis
and bleeding or how to adjust the dose. Notable
additional variables driving bleeding and
thrombosis independent of anti-factor Xa activity
are also present. Reported correlation with renal
function and measured anti-factor Xa activity
is poor. Use of other surrogate markers such as
D-dimer in ESRD, especially with convective
dialysis, has not correlated with measured antifactor Xa activity. Use of UFH may be preferred
in patients with severe renal impairment.
44
• Trough anti-Xa monitoring has been suggested
to evaluate accumulation at the end of the dosing
interval in patients with renal impairment.
Notable assay errors, however, can also be
present and correlation to CrCl has been poor.
It is important to know the timing of anti-Xa
monitoring in relation to the previous dose.
• Various doses of LMWH and DOACs are used for
VTE prophylaxis following orthopedic surgery,
treatment of VTE, and stroke prophylaxis
in atrial fibrillation. Caution is advised in
determining the appropriate dose for the specific
indication.
• Because renal dosing adjustments can be different
secondary to different therapeutic indications,
it is critical for hospitals and health systems
to facilitate easy access to the indication so
pharmacists can ensure correct dosing.
CONSIDERATIONS IN SPECIAL POPULATIONS 263
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• Venous line administration of enoxaparin (1
mg/kg) is associated with higher measured
anti-factor Xa levels at 4 hours than
arterial line administration for prevention of
thrombosis of the dialysis circuit (0.58 vs.
0.39 for hemodialysis and 0.82 vs. 0.39 for
hemodiafiltration; p< 0.001). Thus, lower
doses may be administered if considering venous
administration versus arterial administration.
32
Hepatic Dysfunction
•
Patients with hepatic insufficiency may have intrinsic coagulation abnormalities
that may lead to both increased bleeding and thromboembolic events.
•
Both clotting factors and natural anticoagulants produced in the liver can be
reduced.
•
Clinical studies involving DOACs have largely excluded all patients with ChildPugh class B or C hepatic insufficiency (see Table 11-8). Note the INR is a
component of the scoring system and could create misleading assessments.
•
Limited data are available regarding the use of DOACs in patients with hepatic
impairment.
45-48
TABLE 11-8: Child-Pugh Score for Liver Impairment
Child-Pugh Score 1 2 3
Bilirubin (mg/dL) 1–2 2–3 >3
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Ascites None Mild Moderate
Encephalopathy (grade)
Prothrombin time (seconds prolonged) 1–4 4–-6 >6
a
Encephalopathy grades: Grade 1: disordered sleep, mild confusion; Grade 2: lethargic, moderate
confusion; Grade 3: somnolent but rousable, confused, disoriented; Grade 4: coma, unarousable.
Total the score from the 5 rows. Score interpretation: Class A (mild disease) <7; Class B (moderate
disease) 7–9; Class C (severe disease) 10–15.
a
None 1 and 2 3 and 4
264 Anticoagulation Therapy
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TABLE 11-9: Use in Patients with Hepatic Dysfunction
Agent Parameter Child-
Pugh B
Warfarin INR
Argatroban C
(ng/mL)
max
↑
↑↑
AUC (ng*h/mL)
↑↑↑
(min)
T
1/2
↑↑↑
Bivalirudin C
Dabigatran C
(ng/mL)
max
(ng/mL)
max
↔
↔
AUC (ng*h/mL)
↔
T
(min)
1/2
↔
Use in Moderate
Hepatic Failure
(Child Pugh B)
May need
more frequent
monitoring and
lower doses
Initial dose of 0.5
mcg/kg/min
May need
more frequent
monitoring and
dose adjustments
Patients displayed
large inter-subject
variability; no
evidence of
consistent change
in exposure
Use in Severe
Hepatic Failure
(Child Pugh C)
May need more
frequent monitoring
and lower doses
Initial dose of 0.25
mcg/kg/min
Mild dosing
reductions may be
necessary
Not recommended
45-48
Rivaroxaban C
(ng/mL)
max
↑
AUC (ng*h/mL)
↑↑↑
(min)
T
1/2
↑
Apixaban C
(ng/mL)
max
↔
AUC (ng*h/mL)
↔
(min)
T
1/2
↔
Edoxaban C
(ng/mL)
max
↔
AUC (ng*h/mL)
↔
T
(min)
1/2
↔
*: multiplication sign, AUC: area under the curve, C
INR: international normalized ratio, T
: half-life of a drug in (units of time)
1/2
↑ (20-40%), ↑↑ (41-60%), ↑↑↑ (>60%)
Avoid use Avoid use
No
Not recommended
recommendation
can be provided
Use not
recommended
: maximum drug concentration after a dose,
max
Use not
recommended
CONSIDERATIONS IN SPECIAL POPULATIONS 265
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Caveats for Consideration
•
Argatroban dosing requirements are much lower in patients with hepatic
dysfunction.
hepatic dysfunction.
•
None of the DOAC agents is recommended to use in hepatic dysfunction as
these patients were excluded in clinical trials.
Elderly Patients
•
Elderly patients have an increased prevalence of atrial fibrillation, and rates of
VTE also increase with age.
•
Risk of bleeding may increase in elderly patients receiving anticoagulation due
to low body weight, altered body composition of fatty tissue or muscle, and
higher frequency of renal insufficiency.
TABLE 11-10: Use of DOACs in Elderly Patients
Category Dabigatran Rivaroxaban Apixaban Edoxaban
Patients >75
years old
Manufacturer
recommendation
40% of patients
in atrial
fibrillation trial
9.9% of patients
treated for VTE
and 5.3% >80
years old
The risk of stroke
and bleeding
increases with
age, but the
risk−benefit
profile is
favorable in all
age groups.
15% of patients
in orthopedic
prophylaxis
38% of patients
treated for atrial
fibrillation
16% of patients
treated for VTE
In clinical trials,
the efficacy of
rivaroxaban in
elderly patients
(>65 years)
was similar to
that in younger
patients.
Thrombotic and
bleeding rates
were higher in
older patients,
but the risk−
benefit profile
was favorable in
all age groups.
16% of patients
in orthopedic
prophylaxis
31% of patients
treated for atrial
fibrillation
13% of patients
treated for VTE
No clinically
significant
differences
in safety or
effectiveness
were observed
in different age
groups.
2-5
41% of patients
treated for atrial
fibrillation
14% of patients
treated for VTE
In clinical trials,
the efficacy and
safety in elderly
(>65 years) and
younger patients
were similar.
DOAC: direct-acting oral anticoagulant, VTE: venous thromboembolism
266 Anticoagulation Therapy
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Caveats for Consideration
•
Dabigatran 150 mg BID has demonstrated decreased intracranial bleeding but
increased extracranial bleeding rates; however, the increased extracranial bleed
ing rates are largely due to gastrointestinal bleeding in patients >75 years old
with atrial fibrillation compared to warfarin.
•
Rivaroxaban has significantly less bleeding in elderly patients treated for VTE.
•
Apixaban displayed significantly reduced bleeding rates in patients with VTE
and atrial fibrillation.
•
DOAC agents are associated with lower rates of intracranial hemorrhage
compared to vitamin K antagonists (VKA).
•
Dabigatran, rivaroxaban, and edoxaban are associated with a significant
increased risk of gastrointestinal bleeding when used for atrial fibrillation stroke
prevention.
21,27
• Controversy surrounds the benefit of
anticoagulation in patients with atrial
fibrillation who are at a perceived increased risk
of falling. It has been estimated that a patient
must fall 295 times a year on warfarin before
risks of subdural hematoma outweigh benefits of
stroke prevention.
49
50
-
• In patients prone to falling, modifying the
anticoagulation approach should not be the only
consideration. Other factors such as medications
that may have promoted balance issues, or use of
afternoon diuretics that will result in having to go
to the bathroom late at night unassisted, should
also be considered. Obstacles that can lead to
tripping should be addressed and walking aids
promoted.
• Consider once-daily dosing of anticoagulants,
especially sub-Q administered agents like
enoxaparin, in patients who may have trembling
hands and may not be able to administer doses
appropriately.
• Pill boxes may be beneficial because this
patient population is prone to forgetting to take
medications.
CONSIDERATIONS IN SPECIAL POPULATIONS 267
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Obesity and Low Body Weight
•
The prevalence of obesity (body mass index [BMI] >30 kg/m
substantially over recent years and has now reached 35% of adults in 2010.
such as cardiovascular disease, stroke, and VTE (especially pulmonary embolism
[PE]).
•
Little evidence exists on whether or not a particular medication dose needs to
be increased in obese patients to allow for adequate concentrations to prevent
or treat thromboembolic disease and whether or not the dose should be capped
to prevent any unwanted bleeding from occurring.
•
Patients >150 kg and <50 kg are largely underrepresented in clinical trials. With
population extremes, very small numbers of patients may have been involved
making it difficult to draw solid conclusions on observations.
•
Total body weight is recommended for dosing LMWH.
•
Capping doses of LMWH is not recommended for treatment of VTE.
51-56
2
) has increased
TABLE 11-11: Maximum and Minimum Weights Studied in
Anticoagulant Clinical Trials
Agent Highest Weight Lowest Weight
Enoxaparin 196 kg 45 kg
Dalteparin 190 kg Unknown
Fondaparinux 215 kg Unknown
Tinzaparin 165 kg Unknown
Dabigatran 222 kg 32 kg
Rivaroxaban 209 kg 33 kg
Apixaban 210 kg 28.9 kg
Edoxaban NA NA
NA: not available
268 Anticoagulation Therapy
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TABLE 11-12: Pharmacokinetics of Patients with Obesity or Low
Body Weight
Drug Outcome Weights
Dalteparin Anti-Xa trough <20% IBW
Enoxaparin Mean anti-Xa level <23 kg/m
Tinzaparin Mean Cl (L/hr) >30 kg/m
Fondaparinux Mean Cl (L/hr) <50 kg
Dabigatran Steady-state concentration
Rivaroxaban
Apixaban
1-5,15-17
(ng/mL/mg)
C
(ng/mL)
max
AUC (mcg*h/L)
T
(hr)
1/2
(ng/mL)
C
max
AUC (mcg*h/L)
↔
↑↑
↓
<50 kg
↑
<50 kg
↑↑
↔
↑
<50 kg
↑
↔
>40% IBW
↔
2
2
↑
>100 kg
↓↓
>120 kg
↔
↔
↔
>120 kg
↓↓
↓
Edoxaban Total exposure 13% increase total
↑ (20−40%), ↑↑ (41−60%), ↑↑↑ (>60%), AUC: area under the curve, C
concentration after a dose, IBW: ideal body weight, T
Caveats for Consideration
•
Fondaparinux has a flat dose−response curve so dose adjustments due to
obesity aren’t likely.
•
There is a 30% higher dabigatran concentration in low-weight compared to
high-weight patients.
•
Rivaroxaban demonstrates no real change in pharmacokinetics between patients
with extremes of weight.
•
Apixaban demonstrates roughly a 50% decrease in AUC and t½ in obese patients
compared to patients of low body weight.
•
Apixaban has displayed consistent, reduced rates of bleeding in obese patients
compared to non-obese patients.
(hr)
T
1/2
↑
exposure in 55 kg
weight vs. 85 kg
weight
: half-life of a drug in (units of time)
1/2
↓
: maximum drug
max
CONSIDERATIONS IN SPECIAL POPULATIONS 269
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•
Apixaban dose should be reduced in patients weighing <60 kg (if SCr is >1.5
mg/dL or age >80) who have atrial fibrillation.
•
A reduced dose of edoxaban of 30 mg is recommended in patients with body
weight <60 kg for treatment of VTE.
•
The International Society on Thrombosis and Haemostasis (ISTH) has recently
published guidance statements on the use of DOACs in obesity.
Standard dosing in patients with BMI ≤40 kg/m
DOACs should not be used in patients with a BMI >40 kg/m
57
2
and weight ≤120 kg.
weight >120 kg.
Check drug-specific peak and trough levels if DOACs are
used in this patient population and if the trough is below
the expected range change to a vitamin K antagonist.
•
Bariatric surgery may alter absorption, distribution, metabolism, or elimination of drugs secondary to changes in the gastrointestinal tract anatomy, body
weight, and adipose tissue change.
58
Clinical data on DOACs following bariatric
surgery are nonexistent.
Recommend using a vitamin K antagonist rather than DOACs.
Check drug-specific peak and trough levels if DOACs are used after
bariatric surgery, and change to a vitamin K antagonist if levels are
above or below recommended ranges.
2
or
TABLE 11-13: Potential Dosing of LMWH in Morbidly Obese
Patients
Indication Dalteparin Enoxaparin Tinzaparin Fondaparinux Heparin
VTE
prophylaxis
VTE
treatment
BID: twice daily, LMWH: low molecular weight heparin, q: every, units: International Units, VTE:
venous thromboembolism, x: times
7,500 units
daily
200 units/kg
daily
40 mg BID Not
1 mg/kg
q12 hr
indicated
175 units/
kg daily
2.5 once daily 7,500 units 3 x
10 mg once
daily
daily
80 units/kg
bolus followed
by 18 units/
kg/hr
Caveats for Consideration
•
Enoxaparin 40 mg BID was significantly better than 30 mg BID in patients weighing >50 kg/m
•
Once-daily dosing strategies with enoxaparin should be avoided in obese
patients with VTE based on observations of a notably higher recurrent throm
bosis rate.
•
Capping doses of LMWH is not needed for treatment of VTE. In morbidly obese
individuals, life-threatening thrombosis and PE associated with obesity typically
outweighs the risk for bleeding. Some data suggest that the dalteparin dose
can be split into twice daily as an option.
2
for VTE prophylaxis after bariatric surgery.
60
59
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