Cases & Commentaries

Impatient Inpatient Dosing

Spotlight Case
Commentary By Richard H. White, MD

Case Objectives

  • Appreciate the challenges of initiating
    warfarin therapy in the hospitalized patient
  • Understand the fundamental pharmacology
    of warfarin
  • List the clinical rules for initial
    dosing of warfarin
  • Access resources available to aid
    providers in warfarin dosing

Case & Commentary: Part 1

An elderly man with a diagnosis of acute deep
vein thrombosis (DVT) during a hospital stay was started on
warfarin 5 mg at bedtime and enoxaparin (a low-molecular-weight
heparin).

Warfarin is among the most commonly prescribed
drugs.
Because excessive dosing can lead to major bleeding, it is also
near the top of the list of drugs that lead to serious adverse
events in elderly patients.(1) Physicians
who use warfarin must know its fundamental pharmacology in order to
properly initiate therapy and thereby ensure patient
safety.(2)

Pharmacology of Warfarin

First, warfarin acts by inhibiting the action of
vitamin K, which is required to carboxylate and thereby activate
four clotting factors (II, VII, IX, and X).(3)
This inhibition translates to prolongation of blood clotting times,
measured using the prothrombin time or the international normalized
ratio (INR). Because warfarin inhibits the action of vitamin K,
exogenously administered vitamin K can overcome the effect of
warfarin, leading to synthesis of normal clotting factors with
normalization of clotting.

Second, warfarin is metabolized in the liver by
the P450 cytochrome CYP2C9. It has a half-life of degradation of
approximately 35 hours, which means that when a fixed dose is
administered orally, it takes approximately 7 to 9 days before the
warfarin level or INR reaches a steady state.(4)
Patients with liver disease or patients who take medications that
inhibit CYP2C9 require less warfarin.

Third, warfarin is highly protein bound to
albumin, and it is the free or unbound warfarin level that
interferes with activation of the clotting factors.(5) This means
that hospitalized patients who have a low level of albumin are much
more sensitive to warfarin because there is less protein binding
and thus a higher level of free warfarin.(6)
Patients in the hospital are often very sick, and those with an
albumin level less than 1.8 can be expected to be very sensitive to
warfarin. As patients recover out of the hospital, they generally
require a higher dose of warfarin.

Fourth, there is wide inter-subject variation in
the dose of warfarin required to raise the INR to a therapeutic
level, eg, an INR of 2.5. The average dose is approximately 4.3 mg,
but the range is from 0.5 to 15 mg/day.(7) Older
patients require less warfarin (1% reduction in clearance per year
after age 55), men generally require more than women, and heavier
patients require a higher dose.(8,9)

Fifth, the anticoagulant response to warfarin,
measured using the prothrombin time or INR, is used to determine
the correct dose. It is important to remember that the initial INR
response to warfarin depends not only on the serum level of free
warfarin but also on the rate of degradation of normal clotting
factors, particularly factor VII (half-life of 6 hours).

To summarize, in the elderly patient in this
case, when we initiate warfarin therapy we should expect: (i) a low
maintenance dose of warfarin, perhaps 3 mg/day, and (ii) a 7- to
9-day time lag before the INR reaches steady state. After the first
dose of warfarin, it will take approximately 20 hours before there
is any significant change in the INR (because factor VII levels
first have to fall), so that the INR value measured just 10-12
hours after the first dose is of little clinical use
. In the
average person, the INR value measured the morning after a 5 mg
dose (given at 17:00 pm) is usually normal or less than 1.1. A very
sensitive individual will have an INR of greater than 1.3,
indicating that a maintenance dose of approximately 1 mg will be
needed to achieve the usual therapeutic INR of 2-3.

Clinical Rules for Initial Dosing of
Warfarin

Among hospitalized patients, particularly elderly
patients, start with 5 mg of warfarin. Other factors associated
with lower warfarin requirements include a body mass index (BMI)
less than 20, liver disease (including passive congestion from
congestive heart failure), and being treated with a drug that
inhibits warfarin metabolism (eg, metronidazole,
trimethoprim-sulfamethoxazole, erythromycin, fluconazole,
amiodarone, and others [Table
1
]).(10)

Give the first dose of warfarin as early in the
day as possible, not at 5:00 in the evening. The longer the time
interval between the first dose and the initial INR measurement,
the more the INR will truly reflect the sensitivity to warfarin. If
the time interval is too short, the physician should order another
INR later in the day (at about 3:00 pm) and use this result to
judge the best next dose of warfarin. Optimally, the amount of time
between the first warfarin dose and the INR measurement should be
as close to 20 hours as possible; 12 hours is too short.

In elderly patients, even if the INR on day 2 is
less than 1.1, it is prudent to administer a second dose of 5 mg.
If the patient is young and if the INR on day 2 is less than 1.1
twenty or more hours after the first dose, 10 mg can be given.

Case & Commentary: Part 2

The intern checked the INR the next day and
noted it was 1.0. He increased the warfarin order to 10 mg at
bedtime. The following day, the INR was 1.2. In response, he
increased the warfarin dose again to 15 mg at bedtime. On the
fourth day of warfarin therapy, the INR was 1.8. The intern then
wrote an order for 20 mg at bedtime.

The day 3 morning INR was 1.2 following a 5-mg
dose on day 1 and a 10-mg dose on day 2. This INR value should be
interpreted as reflecting the effect of the initial 5-mg dose.
Using a personal digital assistant (PDA)-based computer-dosing tool
called WARFDOCs, which is based on a previous DOS-based Bayesian
Forecasting program called DrugCalc®(11), the
estimated steady-state dose of warfarin is 3.54 mg, assuming the
patient is 80 years old and weighs 170 pounds. The computer
modeling predicts that if 10 mg is given on each of the next 2
days, the INR value will be 4.0 on day 5, a potentially dangerous
level. Giving even higher doses will lead to an even faster rise in
the INR. WARFDOCs was developed as part of an AHRQ-funded
patient-safety project. The PDA version will be publicly available
soon.

The morning after a 15-mg dose of warfarin was
given on day 3, the day 4 INR was 1.8. The WARFDOCs program
projects that the steady-state dose is still 3.55 mg, and it
predicts that giving just 10 mg on day 4 will result in a
supratherapeutic INR of 3.3 on day 5, rising to an INR of over 7 on
day 6. Because the intern did not have any first-hand experience
dosing warfarin, an even higher dose of 20 mg was administered on
day 4 and, not surprisingly, the day 6 INR was greater than 9.0, a
level at which spontaneous bleeding can occur.

Using the WARFDOCs dosing program (Table 2) to
model this patient’s expected response to a daily dose of 5
mg, we see that the INR is expected to rise slowly but steadily.
The model predicts that it takes 5 days to achieve an INR of just
over 2.0; it would take approximately 12 days to attain the
predicted steady-state INR of 4.7.

If one wanted to shorten the time required to
achieve a therapeutic INR of 2.5, one could give a modestly higher
dose of 7.5 mg on days 4 and 5 and then drop the dose to 3.5 mg
thereafter. This requires considerable experience or use of the
computer software. A better plan would be to exercise patience and
just use low-molecular-weight heparin (LMWH) (as a
“bridge”) for 7 days while the INR rises slowly to
2.32, then stop the LMWH and reduce the warfarin dose to 3 or 4 mg,
testing the INR every few days.

Case & Commentary: Part 3

On day number 6, the INR was over 9.0. The
patient developed an acute episode of bleeding that required
transfusion. Anticoagulation was stopped and vitamin K was
given.

This serious dosing error could have been
prevented in three ways. First, someone experienced in dosing
warfarin should have been supervising this intern. This could have
been a nurse, a hospital pharmacist, the attending physician, or an
anticoagulation nurse/pharmacist specialist.(12,13) Second,
the intern could have used computer modeling.(11,14-16)
Third, the intern could have used a validated nomogram.(17,18) Several
publications have shown that computer modeling of warfarin leads to
more accurate dosing than routine dosing by physicians.(11,19,20)
Finally, data also suggest that a pharmacist’s overview of
anticoagulant care reduces the incidence of adverse
outcomes.(21) Supervision
or primary management of warfarin by a dedicated anticoagulation
pharmacist probably would have prevented this error entirely.

In summary, warfarin dosing is a potentially
dangerous process, particularly in the hospitalized patient. In the
absence of clinical experience, a provider should take advantage of
the expertise of pharmacists or specialized anticoagulation
personnel to aid in dosing decisions. In the near future, this
process will be simplified and made safer with computer-based
management tools. For now, many clinicians will use such tools as
stand-along adjuncts, accessed either through their computers or
hand-held PDAs. Ideally, the WARFDOCs calculator will be integrated
into the hospital or outpatient clinic’s electronic medical
record (EMR) system. When a first-time warfarin dose is ordered,
the computer would capture the demographic data (age, height,
weight, etc.) along with all INR levels and warfarin doses.
Subsequently, each time an INR is measured after warfarin is
administered, the engine would show a steady-state dose prediction
and the expected value of the INR over the next 2 days if the
steady-state dose is given. This would require no work by the
physician, and the program would seamlessly provide data upon which
the doctor could base the next dosing decision. Such a vision may
be realized in many health care organizations in the next few
years.

Richard
H. White, MD
Director, Anticoagulation Service
University of California, Davis

Faculty Disclosure: Dr. White has
declared that neither he, nor any immediate member of his family,
has a financial arrangement or other relationship with the
manufacturers of any commercial products discussed in this
continuing medical education activity. In addition, his commentary
does not include information regarding investigational or off-label
use of pharmaceutical products or medical devices.

References

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Tables

Table 1. Drugs That Alter Response to Warfarin
(22)

List is not all-inclusive; INR should be
monitored after initiating or modifying any drug therapy.

Increase INR

Decrease INR

Erythromycin† Amiodarone† Phenobarbital†
Metronidazole† Cimetidine† Rifampin/Rifabutin†
Fluconazole† Phenytoin* Carbamazepine*
Itraconazole† Dong quai* Vitamin K†
Ketoconazole† Statins* Phenytoin* (chronic use)
SMX/TMP† Alcohol‡ Sucralfate*
Ginseng*
Alcohol‡

*Moderate interaction
†Severe interaction
‡Effect of alcohol on INR is
unpredictable, may increase or decrease INR.

For a detailed review, see (23): Holbrook
AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin
and its drug and food interactions. Arch Intern Med.
2005;165:1095-1106. [
go to PubMed
]

Table 2.
Computer-Predicted INR Response if This Patient Were Given a Daily
Dose of 5 mg of Warfarin

Day

AM INR

PM Dose (mg)

Predicted Steady-State Dose
(mg)

1 1.0 5.0
2 1.05 5.0 3.6
3 1.28 5.0 3.6
4 1.46 5.0 3.6
5 1.75 5.0 3.6
6 2.03 5.0 3.6
7 2.32 5.0 3.6
8 2.61 5.0 3.6