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10 Anticoagulation Therapy
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limit its application. Laboratory results or other surrogate markers may not be
validated to hard outcomes of bleeding, thrombosis, morbidity, or death. Quality
of life or limitations such as the ability to be adherent to the management plan,
affordability of the therapy, or monitoring can influence management plans.
Observations away from the bedside may not always agree with
the patient presentation. For example, increasing the level of
anticoagulation based on laboratory results may not be optimal
if the patient is bleeding. The laboratory test is intended to lend
assistance in determining appropriate patient management and
must not be interpreted apart from the individual patient’s situation.
Caution should be considered with the management of anticoagu
lation therapy when assessing information solely from a computer
screen, even in facilities with the most advanced electronic medical
record systems. Critical information (bleeding, consideration for an
lumbar puncture, potential invasive procedures) may be missed,
due to delay in availability or omission of information. This can limit
the level of care provided. Where possible, bedside or face-to-face
assessments and communication can provide additional information
in real time (current).
Just because something is ordered does not mean the intended
therapy is carried out. Handing out a prescription or order where
hurdles to fulfill the prescription exist may delay or prevent therapy.
A classic example is the patient never filling the prescription when
he or she leaves the hospital.
Even when a patient is handed a dose, this does not always equate
to the patient taking it. In time, this may be discovered by a lack
of INR response to warfarin. One consideration is to ensure the
therapy is administered by requesting a nurse/family member to
witness swallowing of the medication.
When arranging ambulatory anticoagulation patient care follow-
up, has the treatment team determined if the patient can get the
prescribed follow-up laboratory monitoring? Is he or she capable
of utilizing the medication prescribed, including injectables? Is the
patient able to afford the prescribed medication regimen? Longterm regimens should be assessed for financial feasibility, and any
barrier for potential failure identified and addressed. Consider
engaging the community pharmacist in the patient’s care so he or
she can help to ensure a smooth transition.
Communication is critical. All stakeholders need to be aware of any
potential gaps in the therapy when identified.
•
The level of patient acuity should be considered. Clinical trials may not have
explored critically ill patients, yet the therapy may be regularly used in such
a population. Management plans may at times be short term and should be
adapted as changes occur. In many cases, therapy involves multiple agents
or changing settings. A management plan should consider both short- and
long-term goals, and what options are available. Sometimes, the agent chosen
in a management plan may not be the one that is “best” based on evidence,
but instead the agent that is most likely to succeed considering the patient’s
individual situation.
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INTRODUCTION TO ANTICOAGULATION MANAGEMENT 11
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Often, newer agents may be preferable; but if they are financially
prohibitive for the patient, they could lead to suboptimal results.
Patients are often moving in or out of different care settings during
therapy, which can influence the choice of agents utilized in the
management plan.
Management should consider how the patient is clinically changing
in interfering factors (e.g., interacting drugs or disease states) and
adapt as necessary.
When the situation is unclear or rapidly changing, consider short-
term decisions and closer/more frequent assessments.
•
Practitioners who also have practice management responsibilities should strive
to break down transitional care barriers that lead to unsafe care.
When patients are admitted, it is important to obtain an accurate
medication history. This is particularly critical regarding their
antithrombotic drug therapy, which is often taken from electronic
records and may not be current with the patients’ actual regimen.
Effects may last for several days after the last dose was taken,
especially if conditions that reduce elimination are present.
Patients being discharged should be promptly handed off to the
responsible managing clinician, with critical information relayed.
The clinician needs to understand how the inpatient care experience
may have influenced the patients’ antithrombotic therapy needs.
This is a particularly high-risk time period in the patients’ therapy,
and too often patients do not understand their individual manage
ment plans, leading to adverse drug events. Further, it is common
for the medication reconciliation process to not be completed
correctly at discharge. For example, patients can be put back on
their home warfarin dosing (assuming it was correctly identified
at admission!), which is no longer clinically appropriate consider
ing their condition at discharge. Others may revise the regimen
based on an altered response during an acute illness (elevated INR
during acute decompensated heart failure or an infection), and
not re-adjust the dose back once the patient’s baseline has been
reestablished (heart failure or infection resolved). In this situation,
a period of catch up may occur after discharge.
Upon discharge from an acute care setting, consider not only includ-
ing key follow-up information but also identifying the managing
party to have the information sent to them.
•
Each patient is unique and, hence, a special population. However, generalizations
of certain clinical situations create a special management population. Examples
include elderly patients, pediatric patients, critically ill patients, patients with
certain concurrent disease states, patients with a hypercoagulable condition, and
patients with multiple indications for anticoagulation, impaired organ function,
presence of mechanical devices, etc. These patient populations are frequently
discussed in this text. In some selected settings where information may not
directly fit within a specific chapter, it may be found in the Appendix section.
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REFERENCES
1. The Joint Commission National Patient Safety Goals. 2018; https://www.
jointcommission.org/assets/1/6/NPSG_Chapter_HAP_Jan2018.pdf. Accessed May 10,
2018.
Diekemper RL, Patel S, Mette SA, et al. Making the GRADE: CHEST Updates its
2.
methodology. Chest. 2018 Mar;153(3):756-759.
3.
Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of
antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic
Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):53S-70S.
4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST
Guideline and Expert Panel Report. Chest. 2016;149(2):315-352.
5. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the
quality of evidence. J Clin Epidemiol. 2011;64(4):401-406.
6. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the
management of patients with non-ST-elevation acute coronary syndromes: executive
summary: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;130(25):2354-2394.
7. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis
in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch
Intern Med. 2007;167(14):1476-1486.
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Chapter
WARFARIN
Ann K. Wittkowsky
INTRODUCTION
Vitamin K antagonists (VKAs), including warfarin, have been the core of oral anticoagulation for decades. Warfarin is used for stroke prevention in atrial fibrillation,
prevention of valvular thrombosis in biologic and mechanical valve replacement,
and prevention and treatment of deep vein thrombosis, pulmonary embolism, and
other manifestations of venous and arterial thromboembolism. Due to a narrow
therapeutic index, highly variable dose response and the significant impact of
diet, disease, and drugs on warfarin pharmacokinetics and pharmacodynamics, it
is an agent that requires frequent monitoring and dosage adjustment to maintain
its efficacy and safety.
PHARMACOLOGY
Warfarin and other VKAs act by inhibition of the hepatic synthesis of vitamin
K dependent clotting factors II, VII, IX, and X. These clotting factors (and the
anticoagulant substances protein C and protein S) become biologically active
by gamma-carboxylation involving vitamin KH2. In a vitamin K hepatic recycling
process that maintains a continuous supply of vitamin KH2 for clotting factor
synthesis, vitamin KH2 is oxidized to vitamin KO and subsequently converted to
vitamin K by vitamin K epoxide reductase (VKOR) and then back to vitamin KH2 by
vitamin K1 reductase. Warfarin inhibits VKOR and vitamin K1 reductase, resulting
in accumulation of biologically inactive vitamin KO and a reduction in vitamin K
dependent clotting factor synthesis. The full anticoagulant effect of warfarin occurs
when previously activated clotting factors are depleted at rates consistent with their
biologic half-lives, typically within 5–10 days (Table 2-1, Figure 2-1, Figure 2-2).
PHARMACOKINETICS/PHARMACODYNAMICS
Warfarin is a racemic mixture of R and S enantiomers that differ with respect to
elimination half-life, metabolism, pathways of oxidative metabolism, and potency
(Table 2-2). The pharmacokinetic and pharmacodynamic properties of other VKAs
available outside the United States are quite different from those of warfarin
(Table 2-3).
Pharmacogenomic characteristics influence warfarin dosing requirements in a
number of ways.
4
Genetic variations in CYP2C9 genotype can influence the clear-
1
3
13
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TABLE 2-1: Proteins and Half-life
Vitamin K Dependent Proteins Elimination Half-life
Factor II 42–72 hr
Factor VII 4–6 hr
Factor IX 21–30 hr
Factor X 27–48 hr
Protein C 8 hr
Protein S 60 hr
TABLE 2-2: Differences in R and S Enantiomers
R-Warfarin S-Warfarin
Elimination half-life 45 hr (20–70 hr) 29 hr (18–52 hr)
Metabolism 40% reduction
60% oxidation
Oxidative metabolism 1A2>3A4>2C19 2C9>3A4
Potency 1 (reference)
10% reduction
90% oxidation
2.7–3.8 × R-warfarin
TABLE 2-3: Other K Antagonists
Acenocoumarol Phenprocoumon
Elimination half-life R: 9 hr
S: 0.5 hr
Oxidative metabolism R: 2C9>2C19
S: 2C9
Potency R more active due to faster
clearance of S
ance of warfarin, leading to lower-than-average warfarin dosing requirements
in patients who are CYP2C*1/*2, CYP*1/*3, and CYP*2/*3 heterozygotes, and
even lower dosing requirements in CYP*2/*2 and CYP*3/*3 homozygotes. The
*2 and*3 alleles are the primary dysfunctional alleles in patients of European
ancestry, and the *3 allele is most prevalent in patients of Asian ancestry.
Additional polymorphisms, including *5, *6, *8 and *11 alleles, have been
observed in patients of African ancestry.
Haplotype for VKORC1 influences warfarin responsiveness. A minor A
allele in a specific regulatory region of VKORC1, with highest frequency
R: 5.5 days
S: 5.5 days
R: 2C9
S: 2C9
1/3 eliminated unchanged
S 1.5–2.5 × more potent
than R
1 mg Pink 5 mg Peach
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WARFARIN 15
FIGURE 2-1. Jantoven Brand Warfarin Tablets
This color scheme is also used for other brands of warfarin and can be used to
determine a patient’s tablet strength and dose.
Source: Used with permission of Upsher-Smith Laboratories, Inc., Maple Grove, MN.
2 mg Lavender 2.5 mg Green
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3 mg Tan 4 mg Blue
6 mg Teal 7.5 mg Yellow
FIGURE 2-1. (continued)
10 mg White
WARFARIN 17
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% Warfarin steady-state achieved
0
10
20
30
40
50
60
70
80
90
100
Warfarin steady-state
concentration achieved
90
100
Time (hours)
= factor II ; = factor VII; = factor IX; = factor X ; x = warfarin.
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
0
10
20
30
40
50
60
70
80
of clotting factors
% Normal concentration
FIGURE 2-2. Coagulation Factor Decline Over Time
Source: Reprinted with permission from Eckhoff CD, DiDomenico RJ, Shapiro NL. Initiation warfarin therapy: 5 mg versus 10 mg. Annals of
Pharmacotherapy, © 2004; 38:2115-21; reprinted by permission of SAGE Publications, Inc.
18 Anticoagulation Therapy
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in Asians, is associated with lower gene expression and significantly lower
warfarin dose requirements than are seen in patients with the G allele.
Numerous investigations have confirmed that CYP2C9 and VKORC1
genotypes account for 10-45% of variability in warfarin dosing requirements.
A number of dosing algorithms that incorporated CYP2C9 genotype and
VKORC1 haplotype have been investigated, with results suggesting that
pharmacogenetics-guided warfarin dosing might be a promising advance
in clinical care. But recent randomized trials have demonstrated conflicting
results with regard to the influence of genomic-guided dosing on a surrogate
endpoint (time in therapeutic range), and no trial has evaluated meaningful
clinical endpoints. As a result, the use of genetic testing to guide warfarin
dose determination is not a routine component of clinical care.
• When warfarin therapy is started, initial INR
(international normalized ratio) test results
reflect elimination of factor VII. However, the
anticoagulant effect of warfarin is not established
until factors II and X are eliminated. Thus,
when treating acute thrombosis, a bridge with
a traditional immediate-acting anticoagulant
(heparin, LMWH, fondaparinux) is necessary.
• Due to the long half-life of warfarin, every dose
taken within the last 7 days must be considered
when making dosing decisions. However,
doses taken 2–3 days ago will have the most
prominent effect on the current day’s INR, and
these require careful consideration when making
further dosage adjustments.
Vitamin K Interactions
Changes in dietary vitamin K intake can alter response to warfarin therapy.
Accordingly, patients should be instructed to recognize foods high in vitamin
K and to maintain a stable and consistent intake of high vitamin K-containing
foods. Examples of foods high in vitamin K are listed below (Table 2-4). The
USDA Food Composition database can be searched to obtain a thorough
list of foods containing vitamin K. This database is available at: https://ndb.
nal.usda.gov/ndb/nutrients/index.
3
TABLE 2-4: Sample Foods High in Vitamin K
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Broccoli Lettuce
Brussels sprouts Kale
Cabbage Mustard greens
Chard Parsley
Chives Scallions
Collard greens Spinach
Endive Turnip greens
• Hospitalized patients often have changes in
diet, causing fluctuating warfarin requirements
and dosing that is distinctly different from their
outpatient requirements. Further, enteral and
parenteral nutritional supplements containing
vitamin K further complicate matters. It is
important for clinicians to follow changes
in feeding rates and diets as these influence
warfarin dosing.
WARFARIN 19
Disease State Interactions
Numerous disease states influence the pharmacokinetics and pharmacodynamics of warfarin (Table 2-5). Progression and improvement in these
factors can influence warfarin dosing requirements and should be considered
when evaluating INR response to warfarin therapy.
• Patients who experience acute liver dysfunction
(hypotensive episodes, liver metastasis, etc.)
while in the hospital will be extremely sensitive
to warfarin. Vigilance is necessary when
managing warfarin in these patients (daily
INRs and warfarin adjustments), and sometimes
holding warfarin until liver function recovers is
required. Close consultation with the attending
physician is advised in these situations.
• An elevated INR in patients with hepatic
disease does not assure a particular degree of
anticoagulation, as it is associated with broad
impairment of clotting factor synthesis rather
than specific drug-induced changes in vitamin K
dependent clotting factors.
(continued)
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