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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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210 Anticoagulation Therapy
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WARFARIN
• Long half-life of factors II, VII, IX, and X, and protein C and protein S (see Table 2-1).
•
Monitoring of reversal of warfarin using INR. Timing of monitoring the INR after
reversal agent(s) administered depends on the reversal strategy used, the speed
of the onset of reversibility effects, and urgency of need for reversal.
•
Time to reversal and duration of reversal agent effects and potential for rebound
in the INR vary depending on the strategy used for reversal (See Figure 8-1).
•
Monitor PT/INR; in selected cases, Factor II, VII or X can be measured.
VITAMIN K (PHYTONADIONE)
Factors to Consider in Determining a Vitamin K Reversal Dose
•
Pregnancy category C.
•
The liver needs to be capable of producing clotting factors.
•
At higher initial INR values, small changes in clotting factors create larger changes
in the subsequent INR value. Very small amounts of vitamin K (e.g., 0.25–1 mg
IV) can drop a critical INR value (>6) to the target range or lower.
•
It may take more vitamin K to reverse the INR <2 or 1.5 because a greater number
of active clotting factors are needed per INR unit change (see Chapter 21).
•
Large doses of fat-soluble vitamin K can delay reinitiating anticoagulation with
warfarin for days to weeks, potentially requiring bridge therapy; as the severity
of the bleeding increases, the importance of prolonged reversal may diminish
when extended duration of low INRs is desirable.
•
Individuals very sensitive to warfarin dose responses may potentially have larger
INR declines compared to less sensitive patients for the same vitamin K dose.
•
At higher initial INR values, small changes in clotting factors create larger changes
in the subsequent INR value.
•
The parenteral form of vitamin K can be given orally with similar effects on the
INR. This can also allow the use of smaller doses to prevent excessive reversal
(see Table 9-13).
33
32
34
TABLE 9-13: Assessment of Intravenous Vitamin K
Formulation Administered Orally for Non-Urgent Reversal of
Anticoagulation
Initial INR 8 to 11.9 12 to 20 Over 20
Vitamin K dose 2.5 mg 5 mg 5 mg
Day 1 (~14 hr)–INR
• % INR 2–4.9
• % INR <2
INR: international normalized ratio
Note: Differences in clotting factors present between an INR of 8 to >20 is very small.
44
3.5
77%
8%
3
52%
17%
2.9
44%
29%
Thromboembolism
No Bleeding Present, but
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Elevated INR
•
If no invasive procedure is planned,
reversal with vitamin K may not alter
outcomes (see Table 9-14).
35
ANTICOAGULATION REVERSAL: PART II 211
35
Vitamin K Placebo p Vitamin K Placebo p Vitamin K Placebo p
Outcome Day 7 Day 30 Day 90
TABLE 9-14: Assessment of 1.25 mg Vitamin K Orally versus Placebo in Reversal If INR Values Between 4.5–10
in Non-Bleeding Patients
Any bleeding 7.9% 9.2% 0.52 11.5% 12.7% 0.63 15.8% 16.3% 0.86
0.3% 0.3% 1.00 0.6% 0.3% 0.62 1.1% 0.8% 0.72
Major bleeding – – – – – – 2.5% 1.1% 0.22
Death 0 0.3% 1.00 0.3% 1.4% 0.22 2.0% 1.9% 0.94
212 Anticoagulation Therapy
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Procedure/Surgery Planned—INR Reversal Within Hours
•
Intravenous (IV) phytonadione provides a faster decrease in the INR over oral
with some effects observed as early as 4–6 hours after IV administration.
the situation where an emergent drop in anticoagulation that day is desired,
IV vitamin K may be used to reduce degree of anticoagulation for a period of
time after the procedure, but it may not facilitate reaching goals prior to the
procedure. A more rapid-acting agent may be needed to achieve reversal goals
within the same day.
•
Both the IV and oral (PO) route work faster than intramuscular (IM) (risk for
hematoma) and sub-Q (Table 9-15).
4
In
TABLE 9-15: Reversal of Warfarin with Oral versus
Subcutaneous Vitamin K
Mean INR 1 mg Oral
Initial INR 5.6 6.2
INR day 1 2.9 4.2
INR day 2 2.2 3.1
INR day 3 2.7 2.8
INR: international normalized ratio
Note: PO appears to work faster, minimizing any reasons for administering by the SC route.
•
Oral phytonadione provides a decrease in the INR starting within 24 hours (see
Table 9-16).
46
N = 26
1 mg Subcutaneous
N = 25
TABLE 9-16: Reversal of Warfarin with IV versus PO Vitamin K
(Initial INR 6-10)
INR 2.5 mg Orally 0.5 mg Intravenous
Target INR 2–4 6 hr: 0%
45
12 hr: 35%
24 hr: 87%
6 hr: 46%
12 hr: 67%
24 hr: 67%
% INR <2 at 24 hr 9% 29%
% INR >4 at 24 hr 4% 4%
Mean INR at 12 hr 4.4 ± 1.1 3.8 ± 1.4
Mean INR at 24 hr 2.9 ± 0.8 2.6 ± 0.8
hr: hours, INR: international normalized ratio
Notes: IV Vitamin K works faster than PO with effects seen in 6 hours (IV), but similar degree of
reversal (IV and PO) at 24 hours.
ANTICOAGULATION REVERSAL: PART II 213
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•
Approaches to reversing warfarin: Multiple factors should be incorporated into
any plan for reversing warfarin based on
Measured level of anticoagulation (Table 9-17).
Urgency of the situation (Table 9-18).
Ability to sustain goals for bleeding and thrombosis management.
Agents available.
Need for combined rapid onset and potential need for
prolonged duration of effect.
TABLE 9-17: Considerations for Measuring and Reversing
Warfarin
Examples of
Laboratory Assays
to Consider
Pharmacologic
Reversal Agents
Comment
INR/PT
Options include
Factor II or Factor X
Vitamin K (IV or
PO), PCC (3 or 4
factor), FFP
Large amounts of FFP may be required to get
•
close to a normalized INR. INR of FFP is ≤1.3.
Vitamin K doses take 12–48 hours for full effect
•
to be seen.
PCC4 (Kcentra™) dosing:
• Maximum dosing weight 100 kg
INR <2: 12.5–25 units/kg (actual body
weight) (Note: Not included in prescribing
information)
INR 2–4: 25 units/kg (actual body weight)
INR 4.1–6: 35 units/kg (actual body weight)
INR >6: 50 units/kg (actual body weight)
Option: Draw INR and immediately administer
500–1,000 units PCC up front. The balance of the
dose can be administered once the INR is back if the
clinical situation still warrants additional PCC. Some
products have heparin and are not recommended
in the setting of HIT or allergy to heparin. Repeat
INR 10–15 min post-dose and reassess bleeding
presentation as part of the assessment to determine
if additional doses are necessary.
•
Some experience with low dose aPCC: (500–
1,000 units x 1).
36,37
See Chapter 8, Table 8-2.
aPCC: activated prothrombin complex concentrates, FFP: fresh frozen plasma, HIT: heparininduced thrombocytopenia, INR: international normalized ratio, IV: intravenous, PCC:
prothrombin complex concentrates, PCC4: 4 factor prothrombin complex concentrates, PO: oral,
PT: prothrombin time
214 Anticoagulation Therapy
Clinical Scenario
Life-threatening bleeding
Acute situations requiring
invasive procedure within
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ICH: Neurocritical Case Society
22
(continued)
guidelines recommend 50 units/kg
Considered, Not Both
a
Dose for Method of Reversal
Often Used in Combination Addition of Either rFVIIa or PCC (3 or 4) Can Be
FFP Vitamin K rFVIIa PCC
10–40 mcg/kg 25–50 International Units/kg
administered slow
b
10–20 mL/kg IV Up to 10 mg IV
NR 8–50 International Units/kg
Dose-determined by several factors:
over 30 min
• End target INR
Up to 10–15 mL/kg IV
(NR for fluid-overloaded heart failure
• Current INR
• Duration of reversal
patients)
• Dose of warfarin
For INR <3: 0.25–2 mg IV
INR <2: Depending on how fast this
is desired, a slightly higher dose IV or
PO may be considered.
TABLE 9-18: Dose for Method of Reversal
6–24 hr
Minor bleeding NR 1–5 mg PO; dose based on INR NR NR
ANTICOAGULATION REVERSAL: PART II 215
Clinical Scenario
Elective procedure in
greater than 24 hr
The table provides modalities to reverse the effects of vitamin K antagonists. The modalities are not always complete in their reversal but provide strategies to decrease the
drug’s effects.
The vitamin K dose of 10 mg IV assumes a goal for full reversal and limited concerns to reinitiate a vitamin K antagonist for a period of time (>1 week). Consider the risk
for thrombosis, timing of the procedure, and potential rebound with rFVIIa, FFP, or PCC. Doses for these agents just prior to the procedure may provide a higher period of
hemostasis over earlier administration. Vitamin K may be warranted to sustain reversal post procedure.
FFP: fresh frozen plasma, ICH: intracranial hemorrhage, IV: intravenous, PO: oral, rFVIIa: recombinant activated factor VII, NR: not reported, NRL: not recommended, PCC:
prothrombin complex concentrates
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Considered, Not Both
Dose for Method of Reversal
Often Used in Combination Addition of Either rFVIIa or PCC (3 or 4) Can Be
NR NR
1–5 mg PO or 0.25 –1 mg IV; dose
based on INR (Caution: For patients
with higher risk of thrombosis, i.e.,
mechanical cardiac valve replacement
patients.)
FFP Vitamin K rFVIIa PCC
NR
Note: FFP given with vitamin K the
day prior to a procedure in general will
have minimal effects on pre-procedure
INR if any at all compared to vitamin
K alone.
TABLE 9-18: (Continued)
7,38-42
a
b
216 Anticoagulation Therapy
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• At lower INR values, a larger change in the
percent of activated clotting factors is necessary
to see a rise in the value (INR of 2–3 will be
~25–40% of normal). INR values >6 will be
<10% of normal activated clotting factors.
At this level, small changes in the number of
activated clotting factors will lead to larger
changes in the INR.
Because it does not take much of a change in
clotting factors to lower very high INR values
(e.g. >6) back into the target range, a small
increase in the number (or percent of normal)
of clotting factors will lead to a larger drop in
the INR compared to the amount of clotting
factors needed to drop the INR <2, or back to
baseline. Thus, small doses of vitamin K may
drop a high INR into the therapeutic range,
but a larger dose may be necessary to drop
the INR <2.
• The dose of vitamin K to reverse warfarin will
depend on how high the INR is and the targeted
value after reversal. Only a small change in the
percent of activated clotting factors is required
to drop critical values into the target range (and
thus a small amount of vitamin K required)
compared to dropping the INR value below the
therapeutic range or back to baseline where a
larger dose of vitamin K may be considered.
• One strategy to consider when a patient is not
bleeding—but after clinical assessment a decision
is made to expedite dropping the INR to a lower
value (for invasive procedure)—is to administer
a low dose vitamin K dose with a follow-up INR
later (e.g., 12 hours). If the INR has dropped
sufficiently, then no additional dose may be
needed. If not a sufficient drop, the dose can be
repeated. FFP/PCC can also be administered
shortly prior to the procedure.
Note: For a given INR, the value may drop faster
independent of vitamin K in individuals requiring a
higher maintenance dose of warfarin (Figure 9-2).
3
ANTICOAGULATION REVERSAL: PART II 217
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Reversing an elevated INR with vitamin K may depend on the presence of
bleeding. In a recent analysis assessing bleeding and thrombotic–related
outcomes in clinically stable, nonbleeding patients with no plan for an invasive
procedure, use of vitamin K solely to drop the INR was not associated with
improving outcomes (see Table 9-14).
•
Vitamin K 2.5 mg PO appears to be an effective reversal strategy in nonbleeding
outpatients with INR values over 10.
35
43
Using Concentrated Clotting Factors to Reverse
Warfarin
•
•
Note: There may be a point of diminishing returns (which can vary between situa-
•
•
•
•
47,48
Details regarding the various concentrated clotting factors are described in Chapter 8.
Lack of effect in the clinical trial for KCentra may be from delays with consent,
randomization, and administration of agent. In one post-marketing series in the
setting of ICH with warfarin, an INR <1.3 within 4 hours (PCC4 ~average 2,000
units given) was associated with improved long-term outcomes.
tions) for improved ICH related outcomes despite the reversal therapy given.
The longer the period of time post-initial bleeding event, the more limited the
benefits and greater the potential of creating additional management challenges.
Concentrated clotting factors are associated with a higher risk for thrombosis
with effects potentially lasting several days.
Symptomatic thrombosis may not occur for more than a week
post-administration.
Because risk of thrombosis may be a concern, thromboprophylaxis
should be considered as soon as feasible once bleeding concerns
subside.
Dose-ranging trials in bleeding patients are limited. Many earlier reports
included both PCC and surgical interventions, limiting clarity on what drove
the outcomes observed.
Because these are blood-derived products, lot numbers need to be recorded.
The variability of the INR range, dosing determined in clinical trials based on
the common vial size (e.g., 500 units) and not the actual anti-factor IX concen
tration (e.g., 532 units) suggests that dosing should not be delayed for specific
unit calculations. The studies were not conducted in this manner, and any delay
created may impact outcomes.
49
-
218 Anticoagulation Therapy
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• Several PCC products are currently available.
Be familiar with the products available for
use (Table 8-6). Differences between products
do exist. Some products contain additional
substances including heparin, which may
be of concern for patients with a history of
HIT. The duration of effect and potential for
inducing thrombosis may be related to the dose
given. Generally, rFVIIa should be avoided in
individuals receiving a PCC.
RESTARTING ANTICOAGULATION THERAPY
•
Assess risk for thrombosis and bleeding.
•
In the setting of anticoagulation therapy, once issues relative to the bleeding
event or need to reverse the anticoagulants has diminished, it will be important
to assess the risk of bleeding to thrombosis treatment or prevention. Anticoagulation prophylaxis may need to be considered if sufficient risk for VTE
exists (see Chapter 12).
•
In the setting of ICH with warfarin, warfarin therapy should be restarted at some
point in most (but not all) situations.
Potential exceptions (CNS bleeds)
Cerebral amyloid angiopathy (lobar) bleeding
Microvascular risks
Microbleeds on gradient-ECHO magnetic resonance
imaging (MRI)
Primary prevention atrial fibrillation (AF) with low
CHADS2 <4 or CHADS-VASC <5 (Chapter 14)
Anticipated inability to adequately manage anticoagula-
tion therapy
Patient unable to safely use anticoagulation therapy
Time to restart post an ICH may range from immediately to prefer-
ably 7–14 days in the setting of selected high-risk patients (mechanical mitral valve) to 1–2 months in low-risk AF patients. Decisions
on this should carefully explore the risk involved on a continuous
basis (Figure 9-4).
•
Time to restarting anticoagulation post a bleeding event will depend on the
clinical presentation and need for anticoagulation.
For selected circuit patency goals (e.g., left ventricular devices),
continued anticoagulation may be necessary (but at times the target
goals may be lower until bleeding concerns diminish).
ANTICOAGULATION REVERSAL: PART II 219
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• Falling is a frequent reason for stopping
anticoagulation therapy. Occasional falling may
not be a reason to stop anticoagulation therapy
as the risk of the consequences of the fall may
not be as high as the risk for a recurrent bleeding
event. Keep in mind other potential causes for
falling and removing them.
•
Gastrointestinal bleeding (GIB)
Timing of resumption
Patients who never interrupted therapy or resumed
50
therapy within 14 days experienced no thrombosis.
Recurrent GIB: Significantly increased if warfarin
resumed within 7 days.
Death rate was lowest when warfarin resumed between
15 and 90 days (potential optimal time is approximately
14 days).
Resumption less likely: Older patients if the source of the GIB was
not identified.
Resumption more likely with:
Mechanical cardiac valve
Left ventricular assist devices
Bleeding confined to hemorrhoidal bleeding
THROMBOLYTICS
•
No clear antidote exists; however, blood products and antifibrinolytics have
been used.
•
Blood product replacement and replacement of factors (e.g., FFP, cryoprecipitate [if low fibrinogen] and/or packed red blood cells [PRBCs]), especially in
hemorrhage.
•
Thromboelastograms (e.g. TEG or ROTEM – see Chapter 21) may help determine
the level of lysis present and if it is resolving (closing of the tail in the graph
[Chapter, Figure 21-13] would demonstrate cessation of effect).
39
REFERENCES AND KEY ARTICLES*
1. Smythe MA, Dager WE, Patel NM. Managing complications of anticoagulant therapy. J
Pharm Pract. 2004;17:327-346.
*2. Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies
for oral anticoagulants: clinical practice considerations. Am J Health-Syst Pharm.
2013;70:1914-1929.
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