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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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11
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Chapter
CONSIDERATIONS IN SPECIAL
POPULATIONS
Thaddaus Hellwig and William E. Dager
It is widely known that giving various patient populations the same dose of the
same drug may lead to different treatment outcomes. Differences in dose and
response relationships of anticoagulants within various populations may lead to a
decreased thromboembolic effect or increased rates of bleeding. The “one dose
fits all” strategy may not be appropriate for all patient populations. Independently,
these special populations can have risks for bleeding or thrombosis. This chapter
will outline special patient populations in renal dysfunction, hepatic dysfunction,
elderly, obesity, low body weight, and malignancy.
•
The majority of anticoagulant agents are partially or fully eliminated by the kidneys.
•
Patients with renal impairment may be at risk for drug accumulation and increased rates
of bleeding, and the clinician can play a significant role in recommending alternative
agents or recommend dose adjustments.
•
The majority of data concerning anticoagulants in renal disease are in patients with
stable chronic kidney disease, and data are limited regarding the use of anticoagu
lants in patients with altering degrees of renal impairment because this population
was frequently excluded.
•
None of the agents has been formally studied in patients with end-stage renal disease
(ESRD) for their U.S. Food and Drug Administration (FDA)-approved indications, and
patients generally were excluded from clinical trials involving direct-acting oral anticoagulants (DOACs) with a creatinine clearance (CrCl) <25–30 mL/min.
•
In general, as CrCl decreases, bleeding rates increase with anticoagulant therapy.
Renal failure is also associated with drivers for both thrombosis and bleeding (Table
11-1). Other factors less expressive in normal renal function can accumulate to exert
influence (e.g., plasminogen activator inhibitor [PAI-1]).
•
CrCl should be calculated using the Cockcroft-Gault equation using actual body weight
in accordance with the majority of clinical trials; however, use caution in morbidly obese
patients since they weren’t commonly represented in clinical trials.
•
Studies and recommendations for CrCl <30 mL/min may not have included patients
requiring renal replacement therapy, for which dosing should be separately considered.
•
Anticoagulant dosing is specifically impacted by both indication and renal function
(Tables 11-2,
-
11-3, 11-4, 11-5, 11-6, and 11-7).
251
252 Anticoagulation Therapy
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TABLE 11-1: Examples of Factors Influencing Hypercoagulable
or Hemorrhagic Risk in Renal Failure
Drivers for Thrombosis
•
Increased
PAI-1, vWF, homocysteine, fibrinogen, clotting factors, tissue factor expression,
antiphospholipid antibodies
Decreased
•
Antithrombin, protein C and S, p-selectin, phosphatidylserine
High Hgb with ESA use
•
•
Prothrombotic microparticles
Hemodialysis-induced platelet aggregation
•
•
Endothelial changes
History of thrombotic event
•
•
Factors associated with stroke in the setting of atrial arrhythmias
Inadequate prophylaxis during acute risk periods (acute illness)
•
•
Heparin-induced thrombocytopenia (HIT)
Nephrotic syndrome
•
•
Graft thrombosis
Low albumin
Shear stress
Stenosis
Blood stasis
Drivers for Bleeding
• Systemic anticoagulation
Excessive anticoagulation (including excessing dosing as elimination declines, drug
•
interactions)
•
Antiplatelet therapy
Recent use of systemic thrombolytic agent
•
• Anemia (hereditary and acquired), frequent blood draws
• Impaired platelet function (uremia, oxidative, and mechanical stress)
• Vascular tone modulation (increased NO and prostacyclin, inflammation)
• Dialysis circuit (sheer wall stress by dialyzer on platelets)
• Severe hypocalcemia
• Increased fibrinogen fragments
• Defect in vWF
• Advanced age
• Poorly controlled high blood pressure
• History of bleeding events
• Trauma, increased risks for traumatic events
ESA: erythrocyte-stimulating agent, HgB: hemoglobin, NO: nitrous oxide, PAI-1: plasminogen
activator inhibitor – 1, vWF: von Willibrand factor
CONSIDERATIONS IN SPECIAL POPULATIONS 253
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TABLE 11-2: Pharmacokinetic Changes of Anticoagulants in
Patients with Renal Impairment
Drug Dosing Outcome Mild (CrCl
Dalteparin Treatment T
Enoxaparin Prophylactic Anti-Xa levels
Enoxaparin Treatment Mean anti-Xa
Tinzaparin Treatment T
Fondaparinux Treatment T
Argatroban Treatment Css (ng/mL)
Bivalirudin Treatment T
Dabigatran Treatment C
Rivaroxaban Treatment C
Apixaban Treatment C
Edoxaban Treatment AUC (ng*h/
a
In patients on hemodialysis: AUC 2-fold higher compared to control.
b
A single pharmacokinetic study (n=16) in patients on hemodialysis demonstrated a 56% increase
in AUC.
c
A single pharmacokinetic study (n= 8) in patients on hemodialysis demonstrated a 36% increase
in AUC.
d
Peritoneal dialysis or hemodialysis: 93% increase in AUC and T
↑ (20−40%), ↑↑ (41−60%), ↑↑↑ (>60%), *: multiplication sign, AUC: area under the curve,
: maximum drug concentration after a dose, CrCl: creatinine clearance, Css: plasma or serum
C
max
concentration on steady state, NR: not reported, T
(hr) NR NR
1/2
level
(hr) NR NR
1/2
(hr)
1/2
AUC (ng*h/
mL)
(min)
T
1/2
(min) NR
1/2
(ng/mL)
max
AUC (ng*h/
mL)
T
(hr)
1/2
(ng/mL)
max
AUC (ng*h/
mL)
(hr)
T
1/2
(ng/mL)
max
AUC (ng*h/
mL)
T
(hr)
1/2
mL)
(hr)
T
1/2
1-18
50–80 mL/
min)
Moderate
(CrCl 30–50
mL/min)
Severe
(CrCl <30
mL/min)
↑↑↑
↔ ↑
NR
↑↑↑ ↑↑↑
↑↑↑
↑↑
↑ ↑ ↑↑
↔
↔
↔
↔
↔
↔
↔
↔
↑
↑↑ ↑↑↑
NR
↑
↑↑
↔
NR ↔
↔
↔
NR ↔
↑
↑
NR ↑↑↑
↑
of 12.2 hours.
1/2
: half-life of a drug in (units of time)
1/2
↑↑↑
↑↑↑
↑↑↑
↔
↑
↔
↔
↔
↑
↑↑↑
↑↑↑
a
b
c
d
254 Anticoagulation Therapy
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Caveats for Consideration
•
All heparin products have different fragment sizes, and smaller fragments are
generally cleared renally and may accumulate with reduced renal function.
failure tends to be much faster than observed if measured after several doses.
•
Dalteparin may be a good low molecular weight heparin (LMWH) choice in
patients with reduced renal function.
•
It is unknown how much of an increase in a drug’s AUC can occur before a clinically significant increase in bleeding is observed.
•
It is unknown how each drug’s PK is influenced in patients with rapidly changing
CrCl or patients with acute kidney injury, as most studies are primarily in patients
with chronic stable renal disease.
•
Recent trials in prophylaxis have suggested no difference in bleeding between
enoxaparin and heparin for thromboprophylaxis; however, in lower-weight
individuals, the enoxaparin dose could be close to what has been used for
therapy to bridge to warfarin.
•
Drug level monitoring should be considered in patients with rapidly changing
renal function, or anticoagulant choices may be changed to agents with lower
percentages of renal elimination.
•
Often, traditional therapy of unfractionated heparin and/or warfarin are used
in patients with severe renal dysfunction/ESRD due to the ability to monitor
laboratory parameters; however, bleeding complications are still common with
these traditional therapies.
•
Warfarin: Several studies have observed a 20–25% dosing reduction in mildto-severe renal impairment. This could potentially be driven by renal failure
diminishing hepatic metabolism of cytochrome P450 2C19 isoenzyme (CYP
2C19). In the setting of hemodialysis, international normalized ratio (INR) values
should be drawn prior to dialysis and peripheral blood draws avoided as access
can be difficult.
CONSIDERATIONS IN SPECIAL POPULATIONS 255
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b
d
No dose
adjustment
2-4,15-17
a
Apixaban Edoxaban
10 mg every day 2.5 mg BID 30 mg every day
b
220 mg BID
2.5 mg daily 150 mg BID to
d
No dose
adjustment
d
Avoid use
d
provided
Contraindicated Cannot be
c
40 mg once daily
5,000 units once
Renal Function Dalteparin Enoxaparin Fondaparinux Dabigatran Rivaroxaban
TABLE 11-3: Dosing for Venous Thromboembolism Prophylaxis Following Orthopedic Surgery
Standard dosing
if initiated
daily
CrCl >30 mL/min
30 mg once daily
pre-operatively
or 30 mg BID
CrCl <30 mL/min No dose
adjustment
Study dose, not FDA-approved.
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4 inhibitors unless benefit outweighs bleeding risks.
a
Excluded patients with CrCl <30 mL/min in clinical trials.
Derived from pharmacokinetics studies.
b
BID: twice daily, CrCl: creatinine clearance
c
d
256 Anticoagulation Therapy
Renal Function
Standard dosing
Avoid concomitant use with P-glycoprotein inhibitors.
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4 inhibitors unless benefit outweighs bleeding risks if CrCl <80 mL/min.
Non-FDA approved dose.
Dose for CrCl 20−30 mL/min. Anti-Xa monitoring has been a proposed measure of anticoagulant effect in patients.
Patients with CrCl <30 mL/min were excluded from the clinical trials.
Pharmacokinetic data demonstrate a possible 20-30% reduction in dose.
In one single center observation, enoxaparin doses of ~ 0.6–0.7 mg/kg in the setting of hemodialysis was a safe effective bridge to warfarin.
BID: twice daily, CrCl: creatinine clearance, HIT: heparin-induced thrombocytopenia, IV; intravenous, sub-Q: subcutaneous, VTE: venous thromboembolism
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60 mg every
day following
5–10 days of
parenteral
therapy
Extended
treatment to
prevent VTE
recurrence: 60
mg once daily
e
day
day
30 mg every
19-22
Apixaban Edoxaban
10 mg BID for
b
Rivaroxaban
15 mg BID with
a
150 mg BID
5 mg (<50 kg),
1 mg/kg BID or
7 days followed
by 5 mg BID
Extended
treatment to
prevent VTE
food for 21 days
followed by 20
mg every day
Extended
treatment to
following
5–10 days of
parenteral
therapy
Extended
7.5 mg (50−100
kg), 10 mg
(>100 kg)
1.5 mg/kg once
daily
recurrence:
2.5 mg BID after
6 months of
therapy
prevent VTE
recurrence: 20
mg once daily
treatment to
prevent VTE
recurrence: 150
mg BID
No dose
adjustment
No dose
adjustment
e
adjustment
Use with caution No dose
f
No dose
adjustments
See Table 11-5 See Table 11-5 30 mg every
Avoid use
Contraindicated
(See Chapter 18
for use in renal
failure and HIT)
d,g
1 mg/kg once
daily
200 units/kg
daily x 30 days
80 units/kg IV
bolus followed
TABLE 11-4: Treatment Dosing for Venous Thromboembolism
CrCl >50
followed by 150
units/kg daily
for months 2–6
(patients with
malignancy)
by 18 units/
kg/hr
333 units/kg
sub-Q followed
by 250 units/kg
c
100 units/kg
BID
No dose
sub-Q BID
CrCl 30−50 No dose
No dose
adjustment
adjustment
adjustment
adjustment
CrCl <30 No dose
b
c
d
a
f
g
e
CONSIDERATIONS IN SPECIAL POPULATIONS 257
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Caveats for Consideration
•
Dabigatran, rivaroxaban, and apixaban are not renally dose-adjusted for treatment of venous thromboembolism (VTE).
TABLE 11-5: DOAC Dosing for Stroke Prophylaxis in Atrial
Fibrillation
Renal Function Dabigatran Rivaroxaban Apixaban Edoxaban
Standard dosing
CrCl >30
CrCl <30 75 mg BID
ESRD Avoid use
a
Dose of 2.5 mg BID in patients with any two of the following: age >80 years old, body weight
<60 kg, or SCr >1.5 mg/dL.
b
Do not use if CrCl >95 mL/min, increased thromboembolic (TE) outcomes.
c
Avoid use in patients with concomitant P-glycoprotein inhibitors.
d
Dose has not been fully evaluated in clinical trials for patients with CrCl <30 mL/min.
e
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4
inhibitors unless benefit outweighs bleeding risks.
f
Use if patient is maintained on hemodialysis based on a pharmacokinetic study. Clinical efficacy
nor safety studies have not been conducted on chronic therapy in ESRD.
g
Patients with CrCl <25 mL/min were not studied in clinical trials.
h
Use if patient is >80 years old or body weight <60 kg while maintained on hemodialysis.
i
Use in ESRD is associated with increased bleeding and bleeding-related-mortality.
BID: twice daily, CrCl: creatinine clearance, DOAC: direct-acting oral anticoagulant, ESRD: endstage renal disease
23-27
150 mg BID 20 mg every day 5 mg BID or 2.5
c,d
15 mg every
e,d
day
a
mg BID
No dose
adjustment
(note critical
footnote)
i
15 mg every
f,i
day
5 mg BID
2.5 mg BID
60 mg every
b
day
30 mg every day
a
f,g
g,h
Not
recommended
Caveats for Consideration
•
Dabigatran 75 mg twice daily (BID) dosing has not been studied in clinical trials
and was derived from pharmacokinetic modeling studies.
•
Dabigatran 150 mg BID dosing in patient with a CrCl between 30–50 mL/min
may be associated with increased extracranial bleeding events, especially in
elderly patients.
•
Dabigatran 110 mg BID dosing (not FDA-approved) demonstrated lower rates of
bleeding in patients with a CrCl between 30–50 mL/min and might be beneficial
in this CrCl range.
•
In patients with atrial fibrillation and a significant reduction in renal function,
apixaban maintained consistent benefit in lower bleeding rates compared to
warfarin.
258 Anticoagulation Therapy
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•
Edoxaban has demonstrated a significant increase in thromboembolism (TE)
events compared to warfarin in patients with atrial fibrillation and CrCl >95 mL/
min and, therefore, should be avoided in that patient population.
a
15-17,28-31
Primary PCI in
STEMI: 0.75
mg/kg IV bolus
followed by 1.75
mg/kg/hr
STEMI with
fibrinolytics: no
recommendation
TABLE 11-6: Dosing in Acute Coronary Syndromes
Renal Function Dalteparin Enoxaparin Fondaparinux Bivalirudin
Standard dosing Primary PCI: No
recommendation
STEMI with
fibrinolytics: No
recommendation
Primary PCI in
STEMI: Single
IV dose of 0.5
mg/kg and 0.75
mg/kg
STEMI with
fibrinolytic:
(<75 y.o.): 30
mg IV bolus
followed by 1
mg/kg sub-Q
q12 hr
(≥75 y.o.): 0.75
mg/kg sub-Q
q12 hr
(>100 kg and
<75 y.o.): Cap
first two doses at
100 mg
(>100 kg and
≥75 y.o.): Cap
first two doses at
75 mg
Primary PCI in
STEMI (with GP
IIB/IIIa inhibitor):
2.5 mg IV
Primary PCI in
STEMI (without
GP IIb/IIIa
inhibitor): 5
a
mg IV
STEMI with
fibrinolytic: 2.5
mg IV followed
by 2.5 mg sub-Q
daily
NSTEMI: 120
International
Units/kg
sub-Q q12 hr
(maximum dose
of 10,000 units)
NSTEMI: 1 mg/
kg sub-Q q12 hr
NSTEMI: 2.5
mg/kg sub-Q
d
daily
NSTEMI: 0.1
mg/kg IV bolus
followed by
0.25 mg/kg/
hr; at time of
PCI, administer
additional IV
bolus of 0.5 mg/
kg and increase
infusion rate to
1.75 mg/kg/hr
(continued)
CONSIDERATIONS IN SPECIAL POPULATIONS 259
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TABLE 11-6: (Continued)
Renal Function Dalteparin Enoxaparin Fondaparinux Bivalirudin
CrCl <30 Likely no dose
adjustment
b
needed
STEMI with
fibrinolyic: 1 mg/
kg sub-Q once
daily
Contraindicated Primary PCI:
May consider
reduction in
infusion to 1
c
mg/kg/hr
NSTEMI 1 mg/
kg sub-Q once
daily
ESRD Unknown No available
data
Contraindicated Primary PCI:
May consider
reduction in
infusion to 0.25
c
mg/kg/hr
a
At time of PCI, administer additional 50−60 units/kg of UFH.
b
Data for dalteparin in the setting of acute coronary syndrome has not been evaluated to the
extent of enoxaparin.
c
No dose reduction for renal dysfunction was used in clinical trials.
d
Additional 200 International Units of UFH may be used to minimize thrombosis formation on
guide wire.
CrCl: creatinine clearance, ESRD: end-stage renal disease, IV: intravenous, NSTEMI: non-ST-
elevation myocardial infarction, PCI: percutaneous coronary intervention, STEMI: ST-segment
elevation myocardial infarction, sub-Q: subcutaneous
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