Warfarin (AHFS 20:12.04)

22 Pages·2011·0.72 MB·English

Chapter 24
Ann K. Wittkowsky
Warfarin (AHFS 20:12.04)
In 1939, Professor Karl Link at the University of Wisconsin, supported by a grant from the Wisconsin Alumni
Research Foundation (WARF), isolated a coumarin derivative, dicumarol (bishydroxywarfarin), from spoiled
sweet clover. This compound was found to be responsible for hemorrhagic deaths in cattle in the Midwestern
U.S. and Western Canada for over a decade. A similar compound, warfarin, was later synthesized and marketed
as a rodenticide. By 1955, this compound was commercially available as an anticoagulant.1
Since then, warfarin has been established through clinical trials as a therapeutic agent for the prevention and
treatment of venous and arterial thromboembolic disease. Unfortunately, a narrow therapeutic range and a vast
array of drug, disease, and dietary interactions complicate safe use of warfarin. If not properly and respectfully
used, this medication can lead to severe complications.
The antithrombotic effect of warfarin is the result of its interference with the hepatic synthesis of vitamin
K dependent clotting factors II, VII, IX and X. In addition, it interferes with the synthesis of the anticoagulant
proteins C and S. In order for these clotting factors to become biologically active, glutamic acid residues at the
NH2-terminal region of clotting factor precursors must undergo gamma-carboxylation. This process requires
the presence of vitamin KH2, a reduced form of vitamin K. In the process of gamma-carboxylation, vitamin KH2
is oxidized to vitamin KO, an inactive form of vitamin K which is then converted to vitamin K by vitamin K
epoxide reductase (VKOR) and then to vitamin KH2 by vitamin K1 reductase. This vitamin K hepatic recycling
process assures a continuous supply of vitamin KH2 for clotting factor synthesis.2
Warfarin inhibits VKOR and vitamin K1 reductase, resulting in accumulation of biologically inactive vita-
min KO and thus a reduction in vitamin K dependent clotting factor synthesis. However, the biologic effects
of warfarin are not apparent until the previously activated clotting factors are depleted. This depletion takes
place according to the biologic half-life of each clotting factor (Table 24-1).3 Thus, the full anticoagulant effect
of warfarin does not occur for at least 3–7 days after beginning therapy or changing a dose. When warfarin
therapy is discontinued, blood concentrations of the four vitamin K dependent clotting factors gradually return
to pretreatment levels.
Warfarin is monitored not by drug concentration measurements but by therapeutic response to the presence
of the drug in serum. The prothrombin time (PT) or protime, expressed as an international normalized ratio
(INR), describes the time to clot formation. The goal of warfarin therapy is to extend this time sufficiently to
prevent pathologic clotting while minimizing the risk of hemorrhagic complications. An INR of 2–3 is sug-
gested for most indications, although higher INRs may be necessary in other situations such as mechanical
valve replacement.2 The safety and effectiveness of warfarin therapy can by improved by thorough knowledge
of the pharmacokinetic and pharmacodynamic factors that influence its anticoagulant effect.
Table 24-1. Elimination Half-Lives of Vitamin K–Dependent Proteins
Factor Half-Life
II 42–72 hr
VII 4–6 hr
IX 21–30 hr
X 27–48 hr
Protein C 8 hr
Protein S 60 hr
351
352 Clinical Pharmacokinetics
Usual Dosage Range in Absence of Clearance-Altering Factors
Warfarin doses required to reach a therapeutic INR vary considerably among individuals. Although the average
dose to reach an INR of 2–3 is 4 to 5 mg once daily, doses may range from as little as 0.5 mg daily to 20 mg or
more.4 Numerous factors influence dosing requirements, including goal INR, interacting medications, dietary
vitamin K intake, alcohol use, underlying disease states, age, genetic factors, and others.
A number of initiation and maintenance dosing strategies for adults and the elderly have been developed
(see Dosing Strategies), all of which are based on assessment of INR response. Initiation therapy requires as-
sessment of rate of increase in the INR after the first one to three doses of warfarin and until the INR reaches
the lower limit of the therapeutic range, while maintenance therapy adjustments are based on an assessment of
factors that may have led to changes in the INR. A weight-based loading protocol for infants and children has
also been developed.5 Infants and children appear to require lower warfarin doses than do adults.6 A general
description of dosing requirements is provided in Table 24-2.
Dosage Form Availability
Warfarin is currently available in both oral tablet and injectable form. Coumadin is the proprietary form of
warfarin. Each dose strength of Coumadin is readily recognizable by its color (Table 24-3), and all Coumadin
tablets are scored. The 10-mg tablet contains no dye and can be used to differentiate warfarin allergy from dye
allergy in patients who present with mild allergic reactions after initiation of warfarin therapy.
Generic warfarin is available from many commercial sources. The various manufacturers of generic war-
farin have generally continued the same color scheme for tablet size identifications, but there are a few color
modifications as well as tablet shape and size changes. Practitioners should exercise appropriate caution when
counseling patients based on color schemes of the doses.
The U.S. Food and Drug Administration has given generic warfarin products an AB bioequivalence rating,
meaning that the 90% confidence intervals of the rate and extent of absorption of the generic product are within
Table 24-2. Usual Dosage Ranges
Age Initiation Dose Maintenance Dosage
Infants 1 mo–1 yr 0.2 mg/kg/day for 1–4 days Average 0.33 mg/kg/day, based on INR response
Young children (1–6 years) 0.2 mg/kg/day for 1–4 days Average 0.15 mg/kg/day, based on INR response
Children (6–13 years) 0.2 mg/kg/day for 1–4 days Average 0.13 mg/kg/day, based on INR response
Teenagers (13–18 years) 0.2 mg/kg/day for 1–4 days Average 0.09 mg/kg/day, based on INR response
Adults (18–70 years) 5–10 mg once daily for 1–4 days 5 mg (range 1–20 mg) once daily, based on INR response
Geriatrics (>70 years) 2.5–5 mg once daily for 1–4 days 2.5 mg (range 1–20 mg) once daily, based on INR response. Often
lower than for adults
Table 24-3. Coumadin Color Scheme
Coumadin Dosage Size 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
Warfarin 353
80% to 125% of the mean values of the innovator product.7 Randomized controlled trials and observational
studies have typically found no difference in stability of anticoagulant therapy or in the rate of adverse events
when patients are switched from brand to generic warfarin.8–12 Nonetheless, individual patients may experi-
ence changes in therapeutic response. Thus, patients should generally be treated with a single formulation of
warfarin, and changes in product source should be considered when evaluating changes in therapeutic response.
General Pharmacokinetic Information
Warfarin is a racemic mixture of R and S enantiomers, optical isomers that differ significantly with respect to
their pharmacokinetic and pharmacodynamic properties (Table 24-4).13–15 S-warfarin is 2.7–3.8 more potent
than R-warfarin, likely as a result of differences in receptor affinity to vitamin K reductase enzymes.14,16,17
Absorption
Warfarin is nearly 100% bioavailable (F = 1) when taken orally.18 Both oral and intravenous formulations dis-
play similar pharmacokinetic characteristics.19 The drug is rapidly and completely absorbed from the stomach
and proximal small intestine with peak blood concentrations within 0.3 to 4 hr.20 Food decreases the rate but
not the extent of absorption.21
Distribution
Volume of distribution
The volume of distribution (V) for racemic warfarin ranges from 0.11–0.18 L/kg, similar to that of albumin.22,23
The average V for both R and S warfarin is 0.15 L/kg.
Protein binding
Both R and S warfarin are highly (> 98%) bound to plasma proteins, primarily albumin.24 Only the remain-
ing free (unbound) concentration is pharmacologically active. The fraction of a given concentration that is
unbound increases proportionately with decreasing plasma albumin concentrations and is accompanied by
an increase in plasma clearance.25,26 Stereoselective protein binding has been demonstrated, with a range of
98.9% to 100% for S warfarin compared to 98.7% to 99.9% for R-warfarin.27 However, these differences are
unlikely to be clinically significant.
Elimination
Warfarin displays stereoselective metabolism, involving both oxidation by cytochrome p450 enzymes in the
liver parenchyma and reduction to diasteriomeric alcohols.28–33 S-warfarin is approximately 90% oxidized,
primarily by CYP2C9 to S-6-hydroxywarfarin and S-7-hydroxywarfarin formed in a 3:1 ratio, and to a lesser
extent by CYP3A4 to S-4'-hydroxywarfarin and S-10-hdyroxywarfarin. R-warfarin is approximately 60% oxi-
dized by CYP1A2 to R-6-hydroxywarfarin and R-7-hydroxywarfarin, by CYP3A4 to R-10-hydroxywarfarin and
R-4'-hydroxywarfarin, and by CYP2C19 to R-8-hydroxywarfarin.
These inactive oxidative metabolites and reduced alcohol derivatives of warfarin are eliminated by urinary
excretion. Approximately 50% of a dose of racemic warfarin administered orally is recovered in the urine over
9 days, with recovery of 31% of S-warfarin metabolites and 19% of R-warfarin metabolites and only trace
amounts of unchanged drug.31 Table 24-4 shows clearance values for S- and R- warfarin.14,34
A number of genetic variants of CYP2C9 have been identified.35 In comparison to patients who are ho-
mozygous for the wild-type allele (CYP2C9*1*1), patients with a heterozygous (CYP2C9*1*2, CYP2C9*1*3,
CYP2C9*2*3) or homozygous (CYP2C9*2*2, CYP2C9*3*3) presentation of a variant allele display significant
reductions in the metabolism of S-warfarin to 7-hydroxywarfarin. In in vivo studies, the clearance of S-warfarin
is 8% to 42% lower in CYP2C9*1/*2 heterozygotes compared to the homozygous wild-type, and subject with
the CYP2C9*1/*3 genotype have 38% to 63% lower clearance. Comparatively, heterozygous *2/*3 patients
had 70% to 77% lower clearance, and homozygous *2*2 and *3/*3 patients had 68% lower and 38% to 91%
lower clearance rates, respectively.36-40
In response to reduced S-warfarin clearance, patients with variant expression of CYP2C9 have lower warfarin
dosing requirements than patients with the wild-type allele.41-43 Their risk of over-anticoagulation is higher
354 Clinical Pharmacokinetics
during initiation therapy and during maintenance therapy, and they are more likely to experience bleeding
complications of warfarin.43-46
The genetic expression of VKORC1 also influences warfarin dosing requirements. A number of single
nucleotide polymorphisms of VKORC1 have been shown to be associated with interindividual and interethnic
warfarin dosing requirements. The most significant of these are 1173C>T in intron 1 (expressed as CC, CT, or
TT) and 3730G>A (expressed as GG, GA, or AA) in the 3' untranslated region, as well as -1639G>A (expressed
as AA, AG, or GG).47
Initial work in 147 patients followed from initiation of warfarin therapy found that regardless of the pres-
ence of confounding variables, the mean adjusted daily dose of warfarin required to maintain a stable INR was
higher (6.2 mg) among patients with the VKORC1 1173 CC genotype than patients carrying the CT (4.8 mg)
or the TT genotype (3.5 mg).48 Subsequently, 10 common noncoding VKORC1 SNPs were identified, with 5
major haplotypes inferred in 368 patients (119 white, 96 of African descent, 120 of Asian descent), declar-
ing a low-dose haplotype group (A) and a high-dose haplotype group (B).49 The mean maintenance dose of
warfarin for the 3 haplotype group combinations was 2.7 mg/d for A/A, 4.9 mg/d for A/B, and 6.2 mg/d for
B/B. The A haplotype represents more warfarin sensitivity (i.e., less VKOR expressed), and the B haplotype
represents less warfarin sensitivity. Asians had a higher proportion of group A haplotypes, and Africans had a
higher proportion of group B haplotypes.
Half-life and time to steady state
The average elimination half-life of S warfarin is 29 hr and of R-warfarin is 45 hr.13–15,23 Although it takes ap-
proximately five half-lives to reach steady state warfarin concentrations after initiation of therapy or dosage
adjustments, therapeutic steady state is not achieved until the vitamin K-dependent clotting factors have also
reached a new equilibrium.
Dosing strategies
Initiation dosing
Because of wide variability in dosing requirements among patients, the initial dosing of warfarin therapy is
based on the presence or absence of factors that may influence dosing requirement and on the INR response
to initial doses. Large fixed loading doses (10 mg–15 mg daily for several days) and loading doses based on
body weight (1.5 mg/kg), although once favored, are no longer recommended as they increase the risk of both
over-anticoagulation and hemorrhage.50,51 Instead, two general methods for initiation with moderate warfarin
doses are used. These are the “average daily dosing method” and “flexible initiation.”
Average daily dosing method. In an evaluation of over 2000 patients taking stable doses of warfarin for a variety of indica-
tions, the geometric mean dose was 4.57 mg daily, and the arithmetic mean dose was 5.13 mg daily.4 Patients
who do not meet specific criteria that indicate either high or low sensitivity to the effects of warfarin can be
initiated with a dose of 5 mg daily, with INR values checked within 3–5 days. Subsequent doses are based on
Table 24-4. Pharmacokinetic and Pharmacodynamic Characteristics of the Enantiomers
of Warfarin
R-warfarin S-warfarin
Bioavailability 95%–100% 95%–100%
Volume of distribution 0.12–0.22 L/kg 0.11–0.19 L/kg
Protein binding 98.7%–99.9% 98.9%– 100%
Elimination half-life 45 hr (20–70 hr) 29 hr (18–52 hr)
Hepatic metabolism 40% reduction 60% oxidation 10% reduction 90% oxidation 2C9>3A4
1A2>3A4>2C19
Clearance (single dose) 0.0005–0.0073 L/hr/kg 0.0009–0.0079 L/hr/kg
Clearance (multiple dose) 0.001–0.0052 L/hr/kg 0.0015–0.0131 L/hr/kg
Stereospecific potency 1.0 (reference) 2.7–3.8 × R warfarin
Warfarin 355
the response to the INR and the INR is checked again in another 3–5 days. This pattern continues until the
INR is above the lower limit of the therapeutic range, at which time a maintenance dose is selected based on
the doses given to this point.
Patients who are expected to be more sensitive to the effects of warfarin are described in Table 24-5. In these
patients, the average warfarin dosing requirement is likely to be reduced to 1–3 mg daily. Using the average
daily dosing method, patients with any of these characteristics should be initiated with a lower dose (2.5 mg
is often used), with subsequent dosing based on INR response as measured within 3–5 days.
Several algorithms have been developed to assist with dosing decisions after the first few doses of warfarin
have been administered. After four doses of warfarin 5 mg daily, the INR on day 5 was used to predict weekly
warfarin maintenance doses in a scheme by Pengo et al.52 Siguret et al. administered warfarin 4 mg daily for
three doses and used the INR on day 4 to predict maintenance dose in elderly patients.53 Comparatively, the
INR on day 15 after 2 weeks of warfarin 2 mg daily was used to predict maintenance dose requirements in
elderly patients in a scheme by Oates et al.54
Two algorithms have been developed that use two INR values to predict warfarin maintenance dose. Tait
et al. administered warfarin 5 mg daily for 4 days and used the INR on day 5 to select warfarin doses for days
5–7.55 The subsequent INR on day 8 was then used to predict the maintenance dose. Kovacs et al. developed
a similar algorithm using warfarin 10 mg daily for 2 days (Figure 24-1).56 At day 3, the INR was used to guide
dosing on days 3 and 4, and the INR on day 5 was used to guide the next 3 doses. In a study comparing this
algorithm to a previously published 5 mg initiation algorithm, patients who received the 10 mg starting doses
reached the therapeutic range more rapidly than those initiated with 5 mg starting doses, with no difference
in the risk of major bleeding or overanticoagulation.57 However, the patients in this study were relatively
young and healthy outpatients with acute venous thrombosis. Warfarin initiation with 10 mg may lead to
over anticoagulation and increased bleeding risk in older and less healthy patients with other indications for
oral anticoagulation.58 In addition, initiation with 10 mg can cause a rapid depletion of protein C, which may
induce a relatively hypercoagulability.59
Each of these algorithms differs not only in method used to achieve stable dosing, but also in validation
sample size, population studied, time to achieve a therapeutic INR, risk of under- and over-anticoagulation
during initiation therapy, and success in predicting the maintenance dose. None is a “preferred method,” but
all demonstrate the importance of assessment of change in INR as a predictor of eventual warfarin maintenance
dose requirement and the significance of evaluation of underlying factors that may influence warfarin dosing
requirement in individual patients.
Flexible initiation. Hospitalized patients who are available for daily INR testing may benefit from flexible
initiation of warfarin. Several flexible initiation algorithms have been developed, each of which considers the
rate of increase in the INR on a daily basis to inform daily warfarin dose and to predict the maintenance dos-
ing requirements.
The earliest nomogram by Fennerty et al. started with a 10-mg dose followed by daily INR and daily war-
farin adjustments to reach a predicted maintenance dose by day 4.60 This method was successfully applied in
relatively young patients with thromboembolic disease (mean age 52) and in older patients with other indica-
tions for oral anticoagulation (mean age 66).60,61 However, concerns about the use of 10-mg starting doses,
particularly in the elderly, have persisted.
Table 24-5. Factors Likely to Increase Sensitivity to Warfarin
Age >75 Clinical congestive heart failure
Elevated baseline INR Clinical hyperthyroidism
Fever End stage renal failure
Diarrhea Malignancy
Known CYP2C9 variant Following heart valve replacement
Hypoalbuminemia Hepatic disease
Malnutrition Decreased overall oral intake
Drug-drug interactions
356 Clinical Pharmacokinetics
Day-3 INR Days 3, 4 Day-5 INR Days 5, 6, 7
Dose (mg) Dose (mg)
<2.0 15, 15, 15
< 1.3 15, 15
2.0 – 3.0 7.5, 5, 7.5
3.1 – 3.5 0, 5, 5
1.3 – 1.4 10, 10
> 3.5 0, 0, 2.5
<2.0 7.5, 7.5, 7.5
1.5 – 1.6 10, 5
2.0 – 3.0 5, 5, 5
3.1 – 3.5 2.5, 2.5, 2.5
1.7 – 1.9 5, 5
> 3.5 0, 2.5, 2.5
<2.0 5, 5, 5
2.0 – 2.2 2.5, 2.5
2.0 – 3.0 2.5, 5, 2.5
3.1 – 3.5 0, 2.5, 0
2.3 – 3.0 0, 2.5
> 3.5 0, 0, 2.5
<2.0 2.5, 2.5, 2.5
2.0 – 3.0 2.5, 0, 2.5
>3.0 0, 0
3.1 – 4.0 0, 2.5, 0
> 4.0 0, 0, 2.5
Figure 24-1. Warfarin initiation dosing algorithm based on starting with 10-mg
doses on days 1 and 2.
Source: Reprinted with permission from Kovacs MJ, Anderson DA, Wells PS. Prospective assessment
of a nomogram for the initiation of oral anticoagulant therapy for outpatient treatment of venous
thromboembolism. Pathophysiol Haemost Thromb. 2002;32:131-133.
A low-dose flexible initiation nomogram was associated with a lower risk of overanticoagulation in elderly
patients (age >65) compared to a modification of the Fennerty nomogram.62 More recently, an age-adjusted
flexible warfarin initiation protocol was found to be superior to either the Fennerty nomogram or empiric
dosing.63 Further modifications of this age-adjusted flexible initiation protocol have since been published.64
Crowther et al. compared flexible initiation nomograms that started with either 5 mg or 10 mg starting
doses followed by daily INR determination and prediction of the maintenance dose by day 6.65,66 These authors
concluded that the 10 mg initiation was more likely to result in overanticoagulation on each day that INR was
evaluated. These popular algorithms are presented in Table 24-6.
Initiation nomograms that incorporate genetic information
Numerous algorithms that incorporate CYP2C9 and VKORC1 genetic information to predict warfarin dosing
requirement have been published. In a homogenous, racially and ethnically diverse population, they explain
only 37% to 55% of the variation in warfarin dose requirements.67 During the first week of therapy, genotype
alone accounts for 12% of therapeutic dose variability, but over the first several weeks of therapy becomes less
relevant as INR and prior doses increasingly predict therapeutic dose, and genotype information.68 In fact,
much of the information provided by including genetic information in a dose-prediction model is captured
by early INR response.69
A systematic review of small clinical trials that compared genotype-based warfarin dosing to a non-genotype
strategy found no statistically significant difference in bleeding rates, time within therapeutic range, or time to
Warfarin 357
Table 24-6. Flexible Initiation Nomograms for Warfarin
Day INR 5-mg Initiation Dose 10-mg Initiation Dose
1 5 mg 10 mg
2 < 1.5 5 mg 7.5 mg–10 mg
1.5–1.9 2.5 mg 2.5 mg
2.0–2.5 1.0– 2.5 mg 1.0–2.5 mg
> 2.5 0 0
3 < 1.5 5–10 mg 5–10 mg
1.5–1.9 2.5–5 mg 2.5–5 mg
2.0–2.5 0–2.5 mg 0–2.5 mg
2.5–3.0 0–2.5 mg 0–2.5 mg
> 3.0 0 0
4 < 1.5 10 mg 10 mg
1.5–1.9 5–7.5 mg 5–7.5 mg
2.0–3.0 0–5 mg 0–5 mg
> 3.0 0 0
5 < 1.5 10 mg 10 mg
1.5–1.9 7.5–10 mg 7.5–10 mg
2.0–3.0 0–5 mg 0–5 mg
> 3.0 0 0
6 < 1.5 7.5–12.5 mg 7.5–12.5 mg
1.5–1.9 5–10 mg 5–10 mg
2.0–3.0 0–7.5 mg 0–7.5 mg
> 3.0 0 0
Source: Adapted with permission from Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better. Ann Intern Med. 1997;127:332-333.
achieve a stable warfarin dose.70 Large scale, randomized controlled trials are underway to determine whether
pharmacogenomic-based dosing will improve clinical outcomes. However, genotyping is unlikely to be cost-
effective in most patients.71
Maintenance dosing
Once a patient has reached the lower limit of the therapeutic range and is at relative steady state, maintenance
dosing adjustments are frequently required to maintain the INR within the therapeutic range. Numerous factors
influence the stability of therapy, including drug and disease state interactions, dietary vitamin K intake, alcohol
use, activity, stress and many others. These factors and the INR must be evaluated regularly. The frequency of
monitoring and assessment is described in Table 24-7. Dosing adjustments are based on INR results and the
presumed explanation for out of range INRs. For example, a transient cause of underanticoagulation, such as a
missed dose, may be most appropriately managed by simply continuing the usual maintenance dose or giving
a one-time “booster dose” (1.5–2 times the daily maintenance dose) to replace the missed dose. Comparatively,
a more persistent cause of underanticoagulation such as the addition of an interacting enzyme inducer will
require a more permanent dosing increase. Similarly, a transient cause of overanticoagulation such as acute
illness may require holding a dose of warfarin without any change in the long-term maintenance dose. A more
persistent cause of overanticoagulation such as addition of an interacting enzyme inhibitor will require a more
permanent dosing reduction.
When dosing adjustments are required, they are generally in the range of 5% to 20% of the daily dose, or
5% to 20% of the total weekly dose.72 The tablet size(s) available to the patient and the patient’s own concerns
regarding same daily dosing (e.g., 4 mg daily or 28 mg weekly) or alternate-day dosing (2.5 mg Mondays,
Wednesdays, and Fridays, and 5 mg on all other days, or 27.5 mg/wk) must also be considered.73
358 Clinical Pharmacokinetics
A maintenance dosing guideline for a patient with a goal INR of 2–3 is presented in Table 24-8. However,
it is imperative that the adjustments only be made in patients who have already reached the therapeutic range.
The use of maintenance dosing adjustments (e.g., small 5% to 15% changes every 7 days rather than more
aggressive initiation doses) during initiation therapy will significantly prolong the time to reach the lower limit
of the therapeutic range.
Therapeutic Range
Many clinical trials evaluating the effectiveness and safety of warfarin have helped to establish specific INR
ranges for the prevention and treatment of venous and arterial thromboembolism. The American College of
Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy meets every few years
to summarize available literature and develop graded, evidence-based guidelines.74 The therapeutic range for
various indications, as recommended by the 8th ACCP Conference, are listed in Table 24-9.2
Therapeutic Monitoring
Warfarin therapy suppresses the vitamin K dependent clotting factors to different extents. In stable anticoagu-
lated patients, factor II (mean activity 19%; range 9% to 54%) and factor X (mean activity 18%; range 9% to
45%) are suppressed to the greatest extent, compared to factor VII (mean activity 33%; range 16% to 57%)
and factor IX (mean activity 48%; range 26% to 94%).75 But despite considerable variability, mean activity of
all clotting factors is highly predictive of INR.
The intensity of warfarin therapy is monitored by evaluation of the prothrombin time (PT), expressed as
the INR.76 The PT is prolonged by deficiencies in plasma concentrations of clotting factors II, V, VII, and X. It
is measured by adding both calcium and a tissue thromboplastin to plasma, which accelerates activation of the
extrinsic pathway of the clotting cascade. Time to clot formation is read in seconds using various technologies.
Thromboplastins are extracted from various tissue sources and prepared for use as commercial reagents.
Because of lack of standardization among manufacturers of thromboplastins, each reagent is assigned an In-
ternational Sensitivity Index (ISI) that describes its comparison to an international reference thromboplastin
derived from human brain. The ISI is listed in the product information for each lot of thromboplastin.77 The
ISI is used to convert prothrombin time in seconds to the INR, using the formula:
ISI
 PT 
INR= patient 
PT 
 meannormal 
Table 24-7. Frequency of INR Monitoring and Patient Assessment
Initiation Therapy
Flexible initiation method Daily through day 4, then within 3–5 days
Average daily dosing method Every 3–5 days until INR > lower limit of therapeutic range, then
within 1 week
After hospital discharge If stable, within 3–5 days; if unstable, within 1–3 days
First month of therapy At least weekly
Maintenance Therapy
Dose held today in patient with significant overanticoagulation In 1–2 days
Dosage change today Within 1–2 weeks
Dosage change made ≤2 weeks ago Within 2–4 weeks
Routine follow-up of medically stable and reliable patients Every 4–6 weeks
Routine follow-up of medically unstable or unreliable patients Every 1–2 weeks
Warfarin 359
Table 24-8. Warfarin Dosing Adjustment Guidelines for INR Goal of 2–3
INR Dosage Adjustment Guidelines
<1.5 • Consider a booster dose of 1.5–2 x daily maintenance dose
• Consider resumption of prior maintenance dose if factor causing decreased INR is transient [e.g.: missed warfarin dose(s)]
• If dosage adjustment needed, increase maintenance dose by 10%– 20%
1.5–1.8 • 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 [e.g.: missed warfarin dose(s)]
• If dosage adjustment needed, increase maintenance dose by 5%– 15%
1.8–2 • No dosage adjustment may necessary if the last 2 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 x daily maintenance dose
• Consider resumption of prior maintenance dose if factor causing decreased INR is transient [e.g.: missed warfarin dose(s)]
• If dosage adjustment needed, increase maintenance dose by 5%– 10%
2–3 • Desired range
3–3.2 • No dosage adjustment may necessary 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 no represent an increased risk of hemorrhage for the patient
• Consider continuation of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion]
• If dosage adjustment needed, reduce maintenance dose by 5%–10%
• enance dose if factor cau
3.5–3.9 • Consider holding one dose
• Consider resumption of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion]
• If dosage adjustment needed, decrease maintenance dose by 5%– 15%
> 4 • Hold until INR < upper limit of therapeutic range
• Consider use of mini dose (1.0–2.5 mg) oral vitamin K
• Consider resumption of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion]
• If dosage adjustment needed, decrease maintenance dose by 5%– 15%
The mean normal PT is typically 12 seconds for most thromboplastin reagents and is measured by averag-
ing the PT of non-anticoagulated subjects. The INR is the value that would have been obtained if the reference
preparation had been used in the test. In this way, results obtained at different laboratories can be compared
and results from different lots of the same manufacturer of thromboplastin can also be compared.
Variations in thromboplastin sensitivity are due to differences in manufacturing, source, and method of
preparation. More sensitive thromboplastins with ISI values close to 1.0 produces less rapid stimulation of
factor X, resulting in greater prolongation of the PT for a given reduction in clotting factors.78 Less sensitive
thromboplastins activate residual factor X more rapidly and result in a less prolonged PT, despite a comparable
reduction in clotting factors. ISI values range from 0.95 to 2.9, with a higher ISI number indicating a less
sensitive reagent.
Although manufacturers carefully calibrate the ISI values of their thromboplastins, they do not, in most
cases, provide ISI values that are specific to the instrumentation that will be used to measure INR at individual
360 Clinical Pharmacokinetics
Table 24-9. Optimal Therapeutic Range by Indication
Indication Target INR (Range)
Atrial fibrillation 2.5 (2–3)
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 2.5 (2–3)
Valvular heart disease 2.5 (2–3)
Valve replacement, bioprosthetic 2.5 (2–3)
Valve replacement, mechanical
Aortic, bileaflet 2.5 (2–3)
Aortic, other 3 (2.5–3.5)
Mitral, all 3 (2.5–3.5)
laboratories. One means of overcoming this problem is the use of calibrating plasma provided by reagent
manufacturers.79 By using plasma samples with carefully calculated INR values, a laboratory can verify the
correct ISI value for its system.
Although PT is intended to be measured using plasma samples obtained by venipuncture, a number of
point-of-care INR devices have been developed that use whole blood for rapid measurement of INR.80 These
test systems are used in anticoagulation clinics, physician offices, and hospital nursing units, and can be used
for patient self-testing at home.81
Pharmacodynamic Monitoring
Patients treated with warfarin should be routinely monitored for signs and symptoms of the development,
progression, or recurrence of venous or arterial thromboembolism. They should also be assessed regularly
for the development of hemorrhagic complications to warfarin therapy. In addition, factors that influence the
stability of the INR should be assessed on a regular basis. These include changes in dietary vitamin K intake,
prescription and nonprescription medications and dietary supplements, underlying disease states, alcohol
use, activity, the development of acute illness, and others.2 Changes in any of these parameters can influence
the intensity of anticoagulant therapy and increase the risk of hemorrhagic or thromboembolic complications.
INR-related efficacy
After initiation of warfarin therapy, initial elevations in the INR represent depletion of factor VII due to its short
elimination half-life.82 However, the antithrombotic effect of warfarin requires adequate depletion of factors
II and X.83 Since protein C also has a relatively short elimination half life, initial warfarin doses can induce a
relative hypercoagulable state as the anticoagulant effect of protein C is depleted more rapidly than clotting
factors II and X.59 For these reasons, in addition to the known pharmacokinetic properties of warfarin, the
antithrombotic effect of warfarin is delayed for 4–5 days after initiation. For treatment of acute venous throm-
boembolism, warfarin therapy must therefore be overlapped with heparin, a low molecular weight heparin,
a direct thrombin inhibitor or an indirect factor Xa inhibitor during initiation therapy.84 Current guidelines
suggest that this overlap continue for a minimum of 5 days and until the INR is stable and above the lower
limit of the therapeutic range.85
The INR is designed for monitoring long-term anticoagulation therapy and is less valuable for patients dur-
ing the induction phase of oral anticoagulant therapy. It is also less reliable for patients with significant liver
dysfunction, hereditary factor deficiencies, or for screening for bleeding disorders. These conditions require
evaluation of other measures of hemostasis.