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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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20 Anticoagulation Therapy
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TABLE 2-5: Drug-Disease State Interactions
Clinical Condition Effect on Warfarin Therapy
Advanced age Increased sensitivity to warfarin due to reduced vitamin K stores and/or
Pregnancy Teratogenic; avoid exposure during pregnancy
Lactation Not excreted in breast milk; can be used postpartum by nursing
Alcoholism
Liver disease • Possible coagulopathy induced by decreased production of
Renal disease Reduced activity of CYP2C9, with lower warfarin dose requirements
Heart failure Reduced warfarin metabolism due to hepatic congestion
Cardiac valve
replacement
Nutritional status Changes in dietary vitamin K intake (intentional or as the result of
lower plasma concentrations of vitamin K dependent clotting factors
mothers
• Acute ingestion: inhibits warfarin metabolism, with acute elevation
in INR
Chronic ingestion: induces warfarin metabolism, with higher dose
•
requirements
clotting factors, with baseline elevation in INR
Possible reduced clearance of warfarin
•
Enhanced sensitivity to warfarin postoperatively due to
hypoalbuminemia, lower oral intake, decreased physical activity, and
reduced clotting factor concentrations after cardiopulmonary bypass
disease, surgery etc.) alter response to warfarin
3
Use of tube feedings Decreased sensitivity to warfarin, possibly caused by changes in
Thyroid disease
Smoking and tobacco
use
Obesity Increased warfarin dosing requirements observed inconsistently in
Fever Increased catabolism of clotting factors, causing acute increase in INR
Diarrhea Reduction in secretion of vitamin K by gut flora, causing acute increase
Acute infection/
inflammation
Malignancy Increased sensitivity to warfarin by multiple factors
INR: international normalized ratio
absorption or vitamin K content of nutritional supplements
• Hypothyroidism: decreased catabolism of clotting factors
requiring increased dosing requirements
Hyperthyroidism: increased catabolism of clotting factors causing
•
increased sensitivity to warfarin
• Smoking: may induce CYP1A2, increasing warfarin dosing
requirements
Chewing tobacco: may contain vitamin K, increasing warfarin
•
dosing requirements
obese and morbidly obese patients
in INR
Increased sensitivity to warfarin
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• Thyroid status is often not a clinical concern
unless thyroid status is changing. In other
words, stable levothyroxine patients in euthyroid
status should be treated like patients without
thyroid issues. Hypothyroid patients initiated
on levothyroxine or having levothyroxine dose
increases may require warfarin dose reduction.
Patients undergoing hyperthyroid treatment will
likely require warfarin dose increases.
•
Previously stabilized warfarin patients often
have elevated INRs when admitted with
decompensated heart failure. This often requires
holding or reducing their warfarin dose by about
50% for 1–2 days after admission, but as they
diurese and improve, they often require their
previous warfarin dose. Clinicians are often
reluctant to resume previous dosing, thinking
“the dose made them go high,” overlooking the
acute illness as the cause rather than the dose.
As with all warfarin patients, it is important for
the clinician to understand the patient’s complete
clinical status and not just “treat the numbers.”
Drug-Drug Interactions
Numerous prescription and nonprescription drugs as well as natural/herbal
products interfere with the pharmacokinetics and/or pharmacodynamics of
warfarin. The addition or discontinuation of interacting agents can profoundly
impact warfarin dose-response and requires that current medication use be
evaluated routinely in patients taking warfarin so that appropriate monitoring and dosage adjustments may occur. Timely management can avoid
significant interactions and allow for interacting drugs to be used concurrently with warfarin. There is considerable variability in the time of onset,
extent of influence, and time of offset of drug interactions with warfarin,
requiring individualization of dosing and monitoring any time a potentially
interacting medication is started, stopped, or used on an as-needed basis
(Tables 2-6 and 2-7).
5
22 Anticoagulation Therapy
Additive antithrombotic effects
Additive anticoagulant response
INR: international normalized ratio, LMWH: low molecular weight heparin, NSAIDs: non-steroidal anti-inflammatory drugs, SSRIs: selective serotonin reuptake inhibitors
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Decreased catabolism Decreased INR Methimazole Propylthiouracil
Increased catabolism Increased INR Thyroid hormones
Decreased synthesis Increased INR Broad spectrum antibiotics
Increased synthesis Decreased INR Vitamin K
Target Effect Response Examples (Noninclusive)
Clotting
TABLE 2-6: Warfarin Drug Interactions
factors
Inhibition Increased INR Acetaminophen Allopurinol Amiodarone Azole antifungals
Warfarin
metabolism
Cimetidine Fluoroquinolones Macrolides Metronidazole
Propafenone SSRIs Statins Sulfa antibiotics
Nafcillin Phenytoin Primidone Rifampin
Induction Decreased INR Barbiturates Carbamazepine Doxycycline Griseofulvin
Increased bleeding risk Aspirin NSAIDs Salicylates GPIIb/IIIa inhibitors
Increased bleeding risk Heparin LMWH Direct thrombin inhibitors Thrombolytics
Hemostasis
Unknown Decreased INR Ascorbic acid Azathioprine Corticosteroids Cyclosporin
Absorption Reduced Decreased INR Cholestyramine Colestipol Sucralfate
Increased INR Androgens Clofibrate Cyclophosphamide Gemfibrozil
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TABLE 2-7: Indications and Goal INR
Indication Target INR (range)
Atrial fibrillation
Atrial flutter 2.5 (2–3)
Cardioembolic stroke 2.5 (2–3)
Left ventricular dysfunction 2.5 (2–3)
Myocardial infarction 2.5 (2–3)
Venous thromboembolism (treatment and prophylaxis) 2.5 (2–3)
Valvular heart disease 2.5 (2–3)
Valve replacement, bioprosthetic 2.5 (2–3)
Valve replacement, mechanical Also see Chapter 16
Aortic, bileaflet 2.5 (2–3)
Aortic, other 3 (2.5–3.5)
Mitral, all 3 (2.5–3.5)
Other mechanical devices See Chapter 17
INR: international normalized ratio
2.5 (2–3)
1
• Patient and medical staff education on warfarin
interactions reduces hospital admissions by
improving warfarin management and preventing
warfarin misadventures. Hospital admissions
secondary to warfarin drug interactions provide
an opportunity to educate the prescriber, patient’s
outpatient pharmacy, and the patient on
interaction screening.
•
Interactions involving inhibition of S-warfarin
metabolism are more severe and may require
preemptive warfarin dose adjustments or
interchange to safer alternatives. Interactions
involving the less potent R-isomer can often be
managed by daily INR monitoring and usually
cause less dramatic INR elevations.
(continued)
24 Anticoagulation Therapy
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• Clearly determining if a medication, even those
known to interact, caused an INR elevation in
hospitalized patients is difficult because acute
illnesses may also elevate the INR. A good
example is a patient receiving metronidazole for
Clostridium difficile colitis. When an INR bump
occurs, is it from the metronidazole, the severe
diarrhea, poor vitamin K intake, or all of the
above? Often it is a combination of factors, and
the presumed “drug interaction” may become less
pronounced as the patient recovers from illness.
DOSE MANAGEMENT
Dosage Form Availability
Warfarin is available in brand (Coumadin), branded generic (Jantoven), and
various unbranded generic formulations that are 100% bioavailable. The
tablets, which can be crushed, are color coded to identify strength. The
10-mg tablet contains no dyes and can be used for patients in whom dye
allergies are suspected or confirmed (Table 2-8).
Initiation Dosing
After obtaining a baseline INR, which can be used to identify patients with
underlying coagulopathy, warfarin therapy is initiated at a starting dose. Two
general methods of warfarin initiation dosing are available.
TABLE 2-8: Tablet Strengths and Colors (see Figure 2-1)
Tablet Strength Color
1 mg Pink
2 mg Lavender
2.5 mg Green
3 mg Tan
4 mg Blue
5 mg Peach
6 mg Teal
7.5 mg Yellow
10 mg White
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Average Daily Dosing Method
3,6
Although dosing requirements vary considerably among patients, from as
little as ≤1 mg/day to ≥20 mg/day to reach a therapeutic INR of 2–3, the
average dosing requirement is approximately 5 mg daily. The average daily
dosing method for warfarin initiation uses a starting dose of 5 mg daily,
with subsequent dosing adjustments guided by INR response. A well-known
algorithm uses two 5-mg doses and day 3 INR to guide doses on days 3 and
4, following by a day 5 INR to guide doses on days 5–7. An institutional hybrid
using 5 mg daily for 3 days (2.5 mg daily for patients with factors known to
increase sensitivity to warfarin) is described below. This type of initiation is
useful for outpatients, in which daily INR monitoring is inconvenient and can
also be a reasonable starting point for inpatients that are otherwise clinically
stable (Table 2-9).
Flexible Initiation Dosing Nomograms
3,7-9
For inpatients, in which daily INR monitoring is available, a flexible initiation
nomogram can be helpful. Several algorithms have been developed that
utilize daily INR results to guide warfarin dosing for the first 4–6 days of
therapy. These algorithms may begin with either a 5-mg or 10-mg starting
dose, but 10-mg initiation typically results in a higher likelihood of overanticoagulation.
It is critical to appreciate that warfarin dosing nomograms/algorithms have
most often been developed and validated in stable, healthy outpatients.
Many of these studies have significant exclusion criteria (such that a majority
of hospitalized patients were not included) and provide no information on
whether or not changes in interacting drugs were included or considered.
Dosing nomograms offer a reasonable starting point for warfarin dose adjust-
TABLE 2-9: Warfarin Initiation Nomogram
Initial dose
First INR
<1.5
1.5–1.9
2–3
3.1–4
>4 Hold until INR <3 Hold until INR <3
Subsequent dosing
and monitoring
INR: international normalized ratio, x: times
Nonsensitive Patients Sensitive Patients
5 mg every day × 3 days 2.5 mg every day × 3 days
7.5–10.0 mg every day × 2–3 days 5–7.5 mg every day × 2–3 days
5 mg every day × 2–3 days 2.5 mg every day × 2–3 days
2.5 mg every day × 2–3 days 1.25 mg every day × 2–3 days
1.25 mg every day × 2–3 days 0.5 mg every day × 2–3 days
Continue dose escalation and frequent monitoring until lower limit of
therapeutic range is reached.
26 Anticoagulation Therapy
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• Clinicians need to identify factors that may
increase sensitivity to warfarin when initiating
therapy, including interacting medications,
elderly, race, malnutrition, and disease states
like heart failure, acute infections, etc. For these
reasons, acutely ill patients starting warfarin
should be initiated on lower doses such as 2.5–3
mg of warfarin per day.
ments but should never be used in an “absolute” manner. Thorough patient
assessment and clinical judgment are imperative components of warfarin
dose management.
BRIDGING ANTICOAGULATION
Due to the prolonged onset of action of warfarin, it is sometimes necessary
to overlap with a short-acting anticoagulant, typically IV heparin or sub-Q
low molecular weight heparin. This overlap is often referred to as bridging.
When treating acute thrombosis, bridging continues for a minimum of 5 days
and until the INR is greater than the lower limit of the goal INR range. When
no acute thrombosis is involved, bridging can be discontinued once the INR
reaches the lower limit of the therapeutic range, with no minimum duration.
Maintenance Dosing
Once the therapeutic INR range has been reached and warfarin therapy is
essentially at steady state, dosing adjustments are based on routine INR
monitoring and assessment of factors that may have resulted in the INR being
below, within, or above the therapeutic range. Dosing adjustments are based
on percent changes in the weekly (or in some cases, daily) dose, taking into
consideration the tablet size available to the patient. As with initiation therapy
algorithms, maintenance therapy algorithms must be used with considerable
clinical judgment. When the INR test result is unexpected or does not fit the
clinical context, laboratory error should be considered (Table 2-10).
When CYP2C9 and/or VKORC1 genotype information is available for a
patient, these parameters can be incorporated into determining warfarin
maintenance dose. The Clinical Pharmacokinetics Implementation Consortium
provides recommendations and algorithms based on available evidence.
Frequency of INR Monitoring
Frequency of monitoring should be guided by clinical considerations (e.g.,
initiation versus maintenance dosing, stable versus unstable therapy) as well
as by practical issues (e.g., patient convenience, vacations, weekends). If
followup intervals need to be extended for a particular circumstance, a more
conservative dosing strategy may be warranted (Table 2-11).
3
10
1,3
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TABLE 2-10: Warfarin Maintenance Dosing Nomogram
For Goal INR 2–3 Adjustment For Goal INR 2.5–3.5
INR <1.5 •
INR 1.5–1.8 • Consider a booster dose of 1.5–2 times
INR 1.8–1.9 • No dosage adjustment may be necessary
Consider a booster dose of 1.5–2 times
daily maintenance dose.
•
Consider resumption of prior maintenance
dose if factor causing decreased INR is
considered transient (e.g., missed warfarin
dose/s).
If a dosage adjustment is needed, increase
•
maintenance dose by 10–20%.
daily maintenance dose.
Consider resumption of prior maintenance
•
dose if factor causing decreased INR is
considered transient (e.g., missed warfarin
dose/s).
• If a dosage adjustment is needed, increase
maintenance dose by 5–15%.
if the last two INRs were in range; if there
is no clear explanation for the INR to be
out of range; and if, in the judgment of the
clinician, the INR does not represent an
increased risk of thromboembolism for the
patient.
•
Consider a booster dose of 1.5–2 × daily
maintenance dose.
Consider resumption of prior maintenance
•
dose if factor causing decreased INR is
considered transient (e.g., missed warfarin
dose/s).
• If a dosage adjustment is needed, increase
maintenance dose by 5–10%.
INR <2
INR 2–2.3
INR 2.3–2.4
INR 2–3 • Desired range INR 2.5–3.5
INR 3.1–3.2 • No dosage adjustment may necessary if
the last two INRs were in range; if there
INR 3.6–3.7
is no clear explanation for the INR to be
out of range; and if, in the judgment of
the clinician, the INR does not represent
an increased risk of hemorrhage for the
patient.
• Consider resumption of prior maintenance
dose if factor causing elevated INR is
considered transient (e.g., acute alcohol
ingestion).
• If a dosage adjustment is needed, decrease
maintenance dose by 5–10%.
(continued)
28 Anticoagulation Therapy
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TABLE 2-10: (Continued)
For Goal INR 2–3 Adjustment For Goal INR 2.5–3.5
INR
3.3–3.4
INR
3.5–3.9
INR ≥4*
*For management of critically elevated INR and/or serious bleeding, see Table 2-12.
INR: international normalized ratio, x: times
Consider holding ½ –1 dose.
•
•
Consider resumption of prior maintenance
dose if factor causing elevated INR is
considered transient (e.g., acute alcohol
ingestion).
• If a dosing adjustment is needed, decrease
maintenance dose by 5–10%.
• Consider holding 1 dose.
Consider resumption of prior maintenance
•
dose if factor causing elevated INR is
considered transient (e.g., acute alcohol
ingestion).
• If a dosage adjustment is needed, decrease
maintenance dose by 5–15%.
•
Hold until INR <upper limit of therapeutic
range.
Consider use of minidose oral vitamin K.
•
•
Consider resumption of prior maintenance
dose if factor causing elevated INR is
considered transient (e.g., acute alcohol
ingestion).
• If a dosage adjustment is needed, decrease
maintenance dose by 5–15%.
INR 3.8–3.9
INR 4–4.4
INR ≥4.5
• Data on how often INRs are required in the
inpatient setting are scarce. Considering the
instability of patients in high acuity settings,
increased probability of medication interactions,
and changes in dietary intake of vitamin K,
many hospitals often have policies requiring
daily INRs and daily warfarin dosing. This
ensures patients, at least in theory, are reassessed
daily.
• Many hospitals standardize their warfarin
administration time to the evening, so dose
adjustments can be made the same day as an
INR check and to match when most patients take
warfarin at home.
WARFARIN 29
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TABLE 2-11: Frequency of Monitoring by Clinical Setting
Clinical Setting Frequency of Monitoring
Initiation therapy Inpatient initiation Daily
Outpatient flexible initiation Daily through day 4, then within
Outpatient average daily dosing
method
After hospital discharge If stable, within 3–5 days
First month of therapy At least weekly
Maintenance therapy Medically stable inpatients Every 1–3 days
Medically unstable inpatients Daily
After hospital discharge If stable, within 3–5 days
Routine followup in medically
stable and reliable patients
Routine followup in medically
unstable or unreliable patients
Dose held today for significant
over-anticoagulation
Dosage adjustment today Within 1–2 weeks
Dosage adjustment ≤2 weeks ago
INR: international normalized ratio
3–5 days
Every 3–5 days until INR >lower
limit of therapeutic range, then
within 1 week
If unstable, within 1–3 days
If unstable, within 1–3 days
Every 4–12 weeks
Every 1–2 weeks
In 1–2 days
Within 2–4 weeks
Management of Nontherapeutic INRs with or without
Complications
Although general guidelines are available for the management of patients
with nontherapeutic INRs as well as bleeding or thromboembolic complications, some practical issues should be considered too. For patients with
limited access to healthcare or who live in remote areas, it may be advisable to prescribe several tablets of oral vitamin K to have available on an
“as needed” basis. Patients with a significant degree of variability in INR
response may benefit from same-daily dosing of warfarin (5 mg every day,
5.5 mg every day, etc.) rather than alternating dosing (e.g., 7.5 mg Mondays
and Friday, and 5 mg all other days), as well as supplementation with minidose vitamin K (50–100 mcg orally using commercial products available in
health food stores as dietary supplements). Most importantly, the clinical
context of out-of-range INRs needs to be considered before any intervention is made (Table 2-12).
1,11
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