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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5524_Библиотеки_им_академика_М_И_Перельмана.pdf
Mechanism
Drug
Warfarin Vitamin K
of action
epoxide
reductase
inhibition
Table 3. Anticoagulants.
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
— Post-VTE risk
reduction (acute
management of DVT
or PE should be done
with an agent of fast
therapeutic onset).
2–10 mg/d.
See table # for
dosing adjustments.
oral 36 h
(very variable,
range 20–60 h)
(peak plasma
levels reached
72–96 h)
hepatic
(CYP-2C9)
Detection
of anti-
coagula-
tion
biliary INR CYP450: 1A2,
Drug
interactions
2C9, 3A4
inhibitors and
inducers
†
Unique issues
— 2C9 and
VKORC1 genetic
variations influence
dose response and
impact bleeding risk.
— 99% bound to
plasma albumin.
— No hepatic dose
adjustment needed
(however, marked
dose response in
liver desease).
— No renal dose
adjustment needed.
428 E. Gonzalez and E. E. Moore
Heparin
(unfractionated)
Thrombin
and factor
Xa inhibition
(anti Xa/
thrombin
ratio: 1.0)
— VTE prophylaxis.
— DVT and PE
tx (only for acute
management,
transition to
warfarin for post
— VTE risk
reduction).
— NSTEMI or
unstable angina.
— STEMI.
— VTE prophylaxis:
5,000 units q 8–12 h
subq (recommended
dose is 5000 units q8 h;
5000 units q12 h can
be used to minimize
bleeding risk, but efficacy is comparable to
placebo in high VTE
risk patients).
— DVT and PE tx
(only for acute
management, transition
to warfarin for postVTE risk reduction):
80 units/kg bolus i.v.,
then 18 units/kg/h continuous i.v. infusion.
— NSTEMI or unstable angina: 60 units/kg
bolus i.v., then
12 units/kg/h continuous i.v. infusion.
— STEMI: adjunct to
fibrinolysis; 60 units/
kg bolus i.v., then
12 units/kg/h continuous i.v. infusion.
parenteral
(intravenous and
sub-cutaneous)
— i.v. infusion:1.5 h
(increased
with renal
impairment).
— i.v.
bolus (dose
dependent):
25 units/kg =
30 min, 100
units/kg = 60
min.
— subq:
1.5–3.0 h.
hepatic mostly
renal
PTT No significant
interactions
— No hepatic dose
Prevention and Management of Venous Thromboembolism 429
adjustment needed.
— No renal dose
adjustment needed.
— VTE prophylaxis
for BMI ≥40: 7500
units subcutaneous
q8 h.
— Anti-Xa prophylactic goal
(measured 4 h after
dose): 0.1–0.4.
— Anti-Xa
therapeutic goal
(measured 4 h after
dose): 0.3–0.7.
— Relationship
between anti-Xa and
PTT is variable by
institution, however
usually the
therapeutic PTT is
2.0–2.5 times the
control PTT.
(Continued)
Drug
Enoxaparin
(LMWH)
Mechanism
of action
Thrombin
and factor
Xa inhibition
(anti Xa/
thrombin
ratio: 3.3)
Table 3. (Continued)
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
— VTE prophylaxis.
— DVT and PE tx
(only for acute management, transition
to warfarin for postVTE risk reduction).
— NSTEMI or
unstable angina.
— STEMI.
— VTE prophylaxis:
40 mg/d (for ICUtrauma, post-op hip
and knee replacement,
hip and pelvic fracture
patients: 30 mg q12 h).
— DVT and PE tx
(only for acute management, transition to
warfarin for post-VTE
risk reduction): 1 mg/
kg q12 h or 1.5 mg
q24 h.
— NSTEMI or unstable angina: 1 mg/kg
q12 h with concurrent
aspirin tx.
— STEMI: 30 mg
bolus (i.v.), then 1mg/
kg q12 h (subq) (>75
y.o.: no bolus and
0.75 mg/kg q12 h)
parenteral
(subcutaneous)
3.5 h (up to 8 h
in renal
impairment)
hepatic mostly
renal
Detection
of anti-
coagula-
tion
anti-Xa No significant
Drug
interactions
interactions
†
Unique issues
— VTE prophylaxis
for BMI 40–49:
40 mg q12 h, BMI
≥50: 60 mg q12 h.
— No hepatic dose
adjustment needed.
— Avoid if Cr clearance <30 mL/min.
— LMWH efficacy
reduced by vasopressor use.
— Anti-Xa prophylactic goal
(measured 4 h after
dose): 0.2–0.6 (q12 h
or q24 h dosing).
— Anti-Xa therapeutic goal
(measured 4 h after
dose): 0.6–1.0 (q12 h
dosing), 1.0–2.0
(q24 h dosing).
430 E. Gonzalez and E. E. Moore
Dalteparin
(LMWH)
Thrombin
and factor Xa
inhibition
(anti Xa/
thrombin
ratio: 2.0)
— VTE prophylaxis.
— DVT and PE tx
(only for acute management, transition to
warfarin for postVTE risk
reduction(except cancer patients)).
— Post-VTE risk
reduction (cancer
patients only).
— MI (non-Q wave)
or unstable angina.
— VTE prophylaxis:
5000 units/d
— DVT and PE tx:
200 units/kg daily
(transition to warfarin
for post-VTE risk
reduction in noncancer patients).
— Post-VTE risk
reduction (cancer
patients only): 200
units/kg daily for
1 month, then
150 units/kg daily
for months 2–6.
— MI (non-Q wave)
or unstable angina:
120 units/kg Q12 h
(max. dose: 10,000
units q12 h) with concurrent aspirin tx.
parenteral
(subcutaneous)
4 h (up to 8 h in
renal impairment)
hepatic mostly
renal
anti-Xa No significant
interactions
— VTE prophylaxis
Prevention and Management of Venous Thromboembolism 431
for BMI ≥40: 6500
units/d.
— No hepatic dose
adjustment needed.
— Avoid if Cr clearance <30 mL/min.
— LMWH efficacy
reduced by vasopressor use.
— Anti-Xa prophylactic goal
(measured 4 h after
dose): 0.2–0.5.
— Anti-Xa therapeutic goal
(measured 4 h after
dose): 0.5–1.5.
(Continued)
Mechanism
Drug
of action
Bivalirudin Thrombin
inhibition
Table 3. (Continued)
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
— HIT tx.
— PCI for ACS in
HITT or HITT-risk
patients.
— Cardiopulmonary
bypass in HIT
patients.
— HIT tx: 0.1–0.2 mg/
kg/hr continuous i.v.
infusion (goal PTT
2.0–2.5 times control)
(start warfarin once
therapeutic goal
reached and PLT count
≥150 × 10
9
, and continue bivalirudin until
INR within desired
range; stop bivalirudin
and check INR in 4 h,
if INR is below desired
range then resume
bivalirudin and repeat
until desired INR is
reached on warfarin
alone).
— PCI for ACS in
HIT: 0.75 mg/kg bolus
i.v.,1.75 mg/kg/hour
for the duration of procedure and up to 4 h
post-procedure.
parenteral
(intravenous)
25 min (up to
3 h with renal
insufficiency)
blood proteases
20% renal,
proteolysis
Detection
of anti-
coagula-
tion
Drug
interactions
PTT No significant
interactions
†
Unique issues
— Transition to
warfarin may be
delayed based on
bleeding risk and
need for interventional procedures.
— Critically ill
patients require
lower doses.
— No hepatic dose
adjustment needed.
— Renal dose
adjustment required:
CrCL 30–60 mL/
min = 0.08–0.1 mg/
kg/hour; CrCL <30
mL/min = 0.04–
0.05 mg/kg/hour.
— Hemodialysis
removes 25%.
432 E. Gonzalez and E. E. Moore
Argatroban Thrombin
inhibition
Dabigatran Thrombin
inhibition
— HIT tx.
— PCI for ACS in
HIT or HIT-risk
patients.
— Stroke and
systemic embolism
prevention in
non-valvular AF.
— HIT tx and prophylaxis: 0.5–2.0 mcg/kg/
min continuous i.v.
infusion (goal PTT
2.0–2.5 times control)
(start warfarin once
therapeutic goal
reached and PLT count
9
≥150 × 10
continue argatroban
until INR is ≥4; stop
argatroban and check
INR in 4 h, if INR is
below desired range
then resume argatroban
and repeat until desired
INR is reached on
warfarin alone).
— PCI for ACS:
350 mcg/kg bolus i.v.,
25 mcg/kg/min continuous i.v. infusion.
150 mg q12 h oral 16 h hepatic 80% renal,
and
parenteral
(intravenous)
45 min (up to
2 h in hepatic
impairment)
hepatic 22% renal,
65% fecal
20% fecal
PTT No significant
interactions
Ecarin
clotting
time
(ECT) or
thrombin
time (TT)
P-glycoprotein
inhibitors,
PPI**
— Transition to warfarin may be delayed
based on bleeding
risk and need for
interventional procedures.
— Will also
significantly
increase INR.
— No renal dose
adjustment needed.
— Avoid with
impaired liver
function.
— Can be used
(off-label) for
pre-filter
administration
during CRRT in HIT
patients.
— Avoid if Cr clearance <30 mL/min or
with impaired liver
function.
— Dialyzable.
(Continued)
Prevention and Management of Venous Thromboembolism 433
Mechanism
Drug
of action
Fondaparinux Factor Xa
inhibition
(indirect)
Rivaroxaban Factor Xa
inhibition
(direct)
Table 3. (Continued)
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
— VTE prophylaxis.
— DVT and PE tx
(only for acute management, transition to
warfarin for postVTE risk reduction).
— HIT tx.
— VTE prophylaxis
(only for post-op
knee and hip
replacement).
— DVT or PE tx.
— Stroke and
systemic embolism
prevention in nonvalvular AF.
— VTE prophylaxis:
2.5 mg/d.
— DVT or PE tx:
7.5 mg/d (weight
50–100 kg), 10 mg/d
(weight >100 kg).
— HIT tx: 7.5 mg/d
(weight 50–100 kg),
10 mg/d (weight
>100 kg) (start
warfarin once PLT
count ≥150 × 10
continue fondaparinux
for at least 5 days, and
until INR is ≥2 for at
least 24 h).
— VTE prophylaxis:
10 mg/d (14d for knee,
35d for hip)
— DVT or PE tx: 15 mg
Q12 h for 3 weeks then
20 mg/d (duration of tx
per ACCP 9th Ed.).
— Stroke and systemic
embolism prevention
in non-valvular AF:
20 mg/d.
parenteral
(subcutaneous)
9
and
oral 8 h (12 h in
20 h unknown
(non-hepatic)
hepatic 66% renal,
elderly)
Detection
of anti-
coagula-
tion
Drug
interactions
77% renal anti-Xa No significant
interactions
anti-Xa P-glycoprotein
33% fecal
inhibitors,
CYP-3A4
inhibitors
†
Unique issues
— Contraindicated
if body weight
<50 kg.
— Long-term use
(>14 days) has not
been studied.
— Avoid if CrCL
<30 mL/min.
— Dialyzable.
— Anti-Xa prophylactic goal
(measured 3 h after
dose): 0.3–0.5.
— Anti-Xa therapeutic goal (measured 3 h
after dose): 1.2–1.3.
— Avoid if CrCL
<30 mL/min or with
impaired liver
function.
— Not dialyzable
434 E. Gonzalez and E. E. Moore
Apixaban Factor Xa
inhibition
(direct)
P-glycoprotein inhibitors*: rifampin, amiodarone, verapamil. CYP-3A4 inhibitors*: ketoconazole, itraconazole, voriconazole, fluconazole (mostly 2C9 inhibitor, weak 3A4), ciprofloxacin, metronidazole, erythromycin,
ritonavir, amiodarone.
CYP-1A2 inhibitors*: ciprofloxacin, ethanol. CYP-2C9 inhibitors*: amiodarone, TMP/SMX, metronidazole, fluconazole, fluvastatin, isoniazid, lovastatin, setraline, gemfibrozil. CYP-2C9 inducers**: rifampin, carba-
mazepine, phenytoin, phenobarbital.
U.S. brand names: enoxaparin (Lovenox), dalteparin (Fragmin), bivalirudin (Angiomax), dabigratan (Pradaxa), fondaparinux (Arixtra), apixaban (Eliquis), rivaroxaban (Xarelto).
* May increase anti-coagulant concentration and/or effect.
** May decrease anti-coagulant concentration and/or effect.
†
Combination of any two medications that affect hemostasis is considered a significant interaction as they increase bleeding risk.
tx: treatment, DVT: deep vein thrombosis, PE: pulmonary embolism, VTE: venous thrombo embolism, MI: myocardial infarction, STEMI: ST-segment elevation myocardial infarction, NSTEMI: non-ST-segment eleva-
tion myocardial infarction, PTT: partial thromboplastin time, LMWH: low molecular weight heparin, PCI: percutaneous coronary intervention, ACS: acute coronary syndrome,
— Stroke and systemic embolism
prevention in nonvalvular AF.
5 mg Q12 h (2.5 mg if
2 of the following
present: ≥80 y.o,
weight ≤60 kg, or
Cr≥1.5 mg/dL)
oral 12 h hepatic 25% renal,
75% fecal
anti-Xa CYP-3A4
inhibitors
— Avoid if CrCL
<30 mL/min or with
impaired liver
function.
— Not dialyzable
Prevention and Management of Venous Thromboembolism 435
436 E. Gonzalez and E. E. Moore
Table 4. Warfarin dosing.
INR Warfarin daily dose
day 1 5 mg
day 2 <1.5 5 mg
1.5–1.9 2.5 mg
2.0–2.5 1.0–2.5 mg
>2.5 no warfarin
day 3 <1.5 5–10 mg
1.5–1.9 2.5–5.0 mg
2.0–3.0 0–2.5 mg
>3.0 no warfarin
day 4 <1.5 10 mg
1.5–1.9 5.0–7.5 mg
2.0–3.0 0–5.0 mg
>3.0 no warfarin
day 5 <1.5 10 mg
1.5–1.9 7.5–10 mg
2.0–3.0 0–5.0 mg
>3.0 no warfarin
day 6 <1.5 7.5–12.5 mg
1.5–1.9 5.0–10 mg
2.0–3.0 0–7.5 mg
>3.0 no warfarin
*
Consider a first dose of 2.5 mg for patients <50 kg, liver disease, or
of asian ethnicity.
**
Omit doses until INR <2.5.
*
**
**
**
**
**
Prevention and Management of Venous Thromboembolism 437
Table 5. Duration of post-VTE risk reduction therapy.
Venous thromboembolic event Duration of therapy
Provoked DVT (e.g., associated with sur-
3 months
gery, trauma)
Provoked PE (e.g., associated with surgery,
3 months
trauma)
CVC-related DVT 3 months (and as long as CVC is in place)
Idiopathic DVT
Idiopathic PE
*
*
3 months minimum, consider indefinite
3 months minimum, consider indefinite
VTE associated with cancer Indefinite or as long as cancer is active or
requiring therapy
Recurrent VTE Indefinite therapy
**
HIT
without thrombosis 1–3 months
**
HIT
with thrombosis 3–6 months
*
After 3 months of treatment perform hypercoagulable workup and evaluate for risk-benefit ratio of
extended prophylaxis.
**
diagnosis confirmed serologically.
DVT: deep vein thrombosis, PE: pulmonary embolism, CVC: central venous catheter, HIT: heparin
induced thrombocytopenia.