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- Warfarin is a coumarin
that possesses the ability to interfere with the action of vitamin K1.
Specifically, warfarin inhibits the regeneration of reduced vitamin K1
in the liver from the epoxide form of vitamin K. (1)
- By blocking vitamin K
generation, glutamate residues on coagulation factors II, VII, IX and X are
not adequately carboxylated, rendering these coagulation proteins
nonfunctional. (2) (38)
- Thus, warfarin does
not directly inhibit active coagulation, it simply lowers the plasma level
of 4 functional coagulation proteins, making effective coagulation more
- Other vitamin K
dependent proteins inhibited by warfarin include proteins C and protein S,
proteins that are involved in the fibrinolytic system.
- The effect of warfarin
on blood coagulation is measured using an in-vitro coagulation test, either
the prothrombin time (PT) or the better standardized international normalized
- Mathematically, the INR=
(PR)ISI, where the PR is the prothrombin ratio (prothrombin time
divided by the laboratory control prothrombin time) and the ISI is the
international sensitivity index of the thromboplastin reagent. Use of the INR
eliminates variation in PT results between laboratories caused by differences
in the sensitivity thromboplastin reagents. (39)
- Factors that affect the
PT/INR are: a) pharmacokinetic factors, such as changes in the serum level of
warfarin or sudden changes in protein binding, b) pharmacodynamic factors,
particularly the amount of vitamin K1 available in the liver, and
c) laboratory variation in the measurement of the PT/INR.
- Because the half-life
of warfarin is very long (mean t1/2 = 35-40 hours):
a) once a day dosing is sufficient, and
b) the time required to achieve steady-state warfarin levels while taking a
daily maintenance dose is 6-7 days.
- There is very wide
variation between patients in the maintenance dose required to achieve a
specific PT/INR, e.g. an INR between 2.0-3.0. The average dose to achieve this
effect is approximately 4.5 mg/day, but the dose ranges from 1.0 mg/day to
over 20 mg/day. One cannot reliably predict the maintenance dose based on
clinical or demographic parameters alone.
- The drug is highly
protein bound (97-99% when albumin levels are > 3.2 mg/100ml) and only the
"free" drug exerts a biological effect. When the albumin level is low, for
example in post-operative patients or in very sick patients, the level of
amount of free warfarin increases. Hence, sick patients generally require less
warfarin. As the albumin level rises, the maintenance dose rises as well.
- After giving a loading
dose of warfarin, development of the biologic effect requires degradation of
functional clotting factors as well as synthesis of nonfunctioning factors.
The factor with the shortest half-life is factor VII (t1/2 ~ 6
hours) and the factor with the longest half-life is factor II (t 1/2
~ 60 hours). Thus, although low levels functional factor VII may be reached
after just 1-2 days, evidenced by a "therapeutic" anticoagulant response (PT/INR),
reduction of all of the vitamin K dependent clotting factors (antithrombotic
effect) requires many days, hence the need to overlap heparin and warfarin for
at least 5 days. (40,41)
- A large number of
commonly used drugs interact with warfarin in such a manner as to cause either
an appreciable rise in the PT/INR or fall in the PT/INR. These drugs are
listed in Table 5. (42)
Indications for Warfarin.
Specific indications for
warfarin therapy, together with the level of scientific evidence in support of
the use of warfarin are shown in Table 6. (1,43)
Initiation of Warfarin
No foolproof dosing
regimen can be recommended. Dosing must be individualized!
- Giving a large loading
dose of warfarin, e.g. 50 mg, does not hasten establishment of anticoagulation
compared to using a small loading dose, but it dramatically increases the
likelihood of excessive anticoagulation. (44,45) Giving a small loading dose,
e.g. 10 mg a day for the first 1-2 days does not speed up the time required to
achieve a steady state response in most patients, but prolongation of the PT/INR
to dangerous levels occurs in 20% of cases. (46)
- Older age, low
albumin levels and significant comorbid disease, particularly congestive heart
failure and liver disease increase the likelihood that an excessive
anticoagulant will occur after giving 10 mg for two days. In these
individuals, selecting 2.5 to 5.0 mg doses for the first two days is wise.
- Accurate dosing of
warfarin during the first few days of treatment requires either a great deal
of clinical experience or, better, the help of computer-assisted dosing using
a software program [e.g. DrugcalcR, Therapeutic Technologies,
Tallahassee, Fl] that can be kept on a computer in the pharmacy. (22) (47) A
nomogram has been published for dosing warfarin on day 2 and day 3, but the
timing of warfarin administration and the measurement of the PT/INR response
has to match the nomogram, and the accuracy of the nomogram has not been
- A very common dosing
error is to give a 10 mg dose late in the evening, draw a PT/INR early the
next morning (before factor VII levels have had a chance to fall), note a near
normal PT/INR, give another 10 mg of warfarin that night and discover and very
high PT/INR the following morning. Optimally, 20-30 hours should elapse
between the initial dose of warfarin and measurement of the PT/INR response
that you will use to select the second dose of warfarin. For example, if the
first dose is given in the evening, a stat PT/INR should be measured late in
the afternoon the next day, several hours before the next dose is
- The INR 20 hours after
the first dose = 1.3 in an average patient who will require 4.5 mg of warfarin
each day. A higher INR suggests greater sensitivity to warfarin, necessitating
a lower dose.
- If the INR 20 hours
after the first dose is greater than 1.8, the second dose should be held or a
very small dose, e.g. 1 mg, given. If the INR remains in the range from
1.0-1.1 after 24 hours, a second dose of 10 mg can be given. For intermediate
INR values between 1.2-1.8 a second dose between 9.0 mg and 1.0 mg,
respectively, should be selected.
- If the INR remains low
after two doses of 10 mg, a higher third dose (15 or 20 mg) can be given. At
this point computer-assisted dosing is recommended. Suffice to say in some
individuals the slow rise in the INR reflects resistance to warfarin
(maintenance dose is over 12 mg/day) whereas in other individuals the slow INR
rise reflects modest resistance combined with slow degradation of clotting
factors (maintenance dose is between 7-10 mg/day).
Maintenance of Warfarin
- The PT/INR must be
monitored frequently during the initial few weeks of anticoagulation therapy!
- Patients are often
recovering from a significant illness or surgery, and warfarin requirements
change as health improves.
- Drug interactions are
also common as new drugs are often started.
- Optimally, the warfarin
dose should be constant each day. For example, if the dose is approximately 6
mg/day, either a 6 mg tablet or 3 two-mg tablets should be given each day. If
alternate day dosing is selected, the difference between the daily doses
should be kept to a minimum, e.g. 7.5 mg alternating with 5 mg/day. This
minimizes peaks and troughs in the PT/INR response.
- If a pattern of a
stable INR is established, the monitoring interval can be extended for as long
as every month or 6 weeks, but it will require 6 months of more frequent
monitoring to become confident in the longer interval between testing.
- Repeat PT/INR
measurements should be made if a new drug is started or if the patient's INR
- Several studies have
evaluated mini-dose warfarin, e.g. a fixed dose of 1 mg/day, for prevention of
thromboembolism. One study suggested that this dose may be effective in
preventing upper extremity DVT in patients with central catheters, (50)
however a more recent study suggests that it has only marginal efficacy.
- Mini-dose warfarin is
clearly ineffective following high-risk orthopaedic surgery. Recent
data have also shown that mini-dose warfarin is ineffective (together with
aspirin)in high risk patients with atrial fibrillation. (51)
- Mini dose warfarin may
be modestly effective in breast cancer patients being given chemotherapy. (52)
However, there are no widely accepted indications for mini-dose warfarin!
Standard dosing (target INR= 2.5) should be your strategy.
- The efficacy of
warfarin in preventing post-operative deep vein thrombosis has been most
rigorously studied in high-risk orthopaedic patients undergoing total hip
replacement and total knee replacement. (53,54,55,56)
- Warfarin is given the
evening before surgery (10 mg or 5 mg) and either no warfarin or 5 mg is given
the evening after surgery. In randomized controlled trials, warfarin appears
to be as effective as standard dose heparin or LMWH in preventing proximal
deep vein thrombosis following total hip replacement. (54) Warfarin may be
somewhat less effective in preventing calf-vein thrombosis following total
knee replacement. (35)
- Use of warfarin is
associated with a comparable or lower rate of major bleeding and a somewhat
higher incidence of calf-vein thrombosis compared to low molecular weight
heparins. (this is no surprise since its effect takes 2-4 days to begin.)
of Warfarin Therapy.
Patients on chronic
warfarin occasionally require major surgery. (57)
- If the risk of
hemorrhagic complications of the procedure/surgery is low:
a) Dental procedures such as simple restorations, subgingival scaling, simple
extractions and local and regional injections of anesthesia. Multiple
extractions or extensive oral surgery poses a higher risk of bleeding - see
b) Eye surgery such as cataract surgery, vitreoretinal surgery or
trabeculectomy. Orbital surgery or complex lid or lacrimal surgery poses a
higher risk of bleeding - see below. (76,77)
- If the risk of
hemorrhagic complication is high and the risk of thrombosis is low (e.g.
remote hx of DVT, atrial fibrillation without multiple risk factors for
stroke) warfarin can be discontinued 90-115 hours (skip 3 or 4 doses) before
- If the risk of
hemorrhagic complication is high and the risk of thrombosis is high (e.g.
mechanical valve, early stages of treating DVT) the effect of warfarin can be
safely reversed by:
- stop warfarin 2 days
- administer a small
dose of vitamin K, 1-2 mg PO or SC, admitting the patient to the hospital
and starting intravenous heparin 6 ?10 hours later,
- continue heparin for
- discontinue the
heparin 3?6 hours prior to surgery,
- check INR morning of
surgery and proceed with surgery if INR <1.5
- restart heparin
(consider LMWH, given subcutaneously) postoperatively as soon as the risk of
hemorrhage is felt to be low, and then
- reinitiate warfarin
therapy, hopefully as an outpatient, stop heparin once INR therapeutic.
- discontinue warfarin
either 4 days (for INR close to 2.0) or 5 days (for INR close to 3.0) before
surgery and start LMWH (therapeutic dose, such as enoxaparin 1 mg/kg q 12)
the following day,
- give last dose of the
LMWH 24 hr. before surgery
- restart heparin
(especially LMWH, given subcutaneously) postoperatively as soon as the risk
of hemorrhage is felt to be low, and then
- reinitiate warfarin
therapy as an outpatient, stop heparin once INR therapeutic.
These time and resource
consuming regimes are probably not needed are they cost effective in most
patients. Nevertheless, the standard of practice is to employ one of these
regimens if the patient is deemed to be at high risk for thrombosis.
Risk Factors for
Bleeding During Warfarin Therapy.
- Age - Most
studies have demonstrated an increased risk of bleeding in older patients. A
review published in 1995 found seven studies, enrolling a total of 14,388
patients, that showed that elderly patients are twice as likely to have
bleeding complications as younger patients.(30) The review also noted seven
other studies enrolling 2940 patients in which the elderly did not have an
increased risk for bleeding. The discrepancy of these findings likely results
from differences in the patient population in these studies. A 1996 report
that examined 2376 patients attending anticoagulation clinics concluded that
elderly patients up to age 80 were not at increased risk for bleeding. (84)
Those patients over age 80 had a increased risk (relative risk 4.6) of
bleeding compared to younger patients. Although old age alone should not be
considered an absolute contraindication for anticoagulation, these data
suggest that age should clearly be considered when judging the overall risks
and benefits of anticoagulation in the individual.
- Intensity of
anticoagulation - Several controlled and observational studies have noted
that the intensity of anticoagulation is associated with the risk of
hemorrhage, with bleeding approximately three times as common in patients
treated more intensively (INR 3.0 to 4.5) compared to less intensively (INR
2.0 to 3.0).(83) Studies from Europe of patients with mechanical heart valves
indicate that the risk of bleeding does not increase significantly until the
INR rises above 5.0.(86) The discrepancy between these findings in Europe and
;the United States is unclear, but may relate to the definition of significant
- Variability of
anticoagulation - Variability or fluctuation of the INR has also shown to
be a predictor of bleeding. Patients who required more than four dosage
adjustment per year bled in one study 25% more than patients who had fewer
adjustments.(80) This variability may be secondary to patient noncompliance,
dietary influences in vitamin K intake, medication changes, or fluctuations in
the patient's coexisting illnesses.
- History of
cerebrovascular disease - Most studies have found that a history of
cerebrovascular disease is an independent risk factor for intracranial
hemorrhage while anticoagulated. (81) A recent case-control analysis found
that a history of stroke was associated with a three-fold increase for
intracranial hemorrhage. Another study found a history of stroke is
associated with a relative risk of 6.6 for intracranial hemorrhage.
- History of
gastrointestinal bleeding - Past gastrointestinal bleeding, not peptic
ulcer disease alone, has been associated with an approximate three fold
increased risk of anticoagulant-related bleeding. Previous gastrointestinal
bleeding during warfarin therapy is a major risk factor for bleeding.(85)
- Hypertension -
Patients with treated hypertension are probably not at higher risk. Studies
that have controlled for age and history of stroke have not found
hypertension to be an independent predictor for hemorrhage.
- Cancer -
Although most older series report an increase association of bleeding in
patients with cancer, a more recent report has shown no increase risk. This
recent study did, however, note that therapeutic INR's were more difficult
- Hepatic disease
- Liver disease has not been shown to increase the risk of bleeding,
although, this may be due to the reluctance of physicians to start
anticoagulants in patient with severe hepatic dysfunction.
- Alcoholism -
It is also difficult to demonstrate an association with alcoholism and
anticoagulant-related bleeding because the diagnosis of alcoholism is often
inaccurate and when diagnosed correctly, physicians are reluctant to start
an alcoholic on warfarin.
Evaluation of the
Anticoagulated Patient who has a GI or GU Bleed.
Approximately 5% of
anticoagulated patients without a history of prior bleeding may have
gastrointestinal (GI) hemorrhage and 3% of patients may have
genitourinary (GU) hemorrhage. Should the anticoagulated patient who has either
GI or GU bleeding be evaluated for the specific cause of bleeding? Several
studies have attempted to answer this question.
- GI bleeding -
diagnostic evaluations using upper and lower endoscopy uncovered the source of
bleeding between 40 and 80% in these studies. Upper tract sources were usually
from peptic ulcer disease and lower tract from diverticular disease or polyps.
GI malignancies were discovered between 4 and 6% of the patients in each of
the studies. When the three studies were combined, 143 patients had 7
malignancies; one esophageal, two gastric, and four colorectal cancers.
- GU bleeding -
there was also a high success rate in finding abnormalities among
anticoagulated patients with hematuria. (82) Of 32 patients with two episodes
of GU bleeding (the criteria for starting a work-up in this study),
abnormalities were found in 27. Sixteen had infections and 2 had malignancies.
Other causes included renal cyst (n=6), nephrolithiasis (n=2), and papillary
necrosis (n=1). In another study, 6 of 18 patients were found to have an
abnormality explaining their hematuria, one patient had a malignancy.
- Work-up - The
decision to initiate diagnostic testing should be individualized for the
specific patient. Anticoagulated patients, particularly young patients, who
have no risk factors for malignancies may have extensive testing deferred if
the bleeding is felt to be likely self-limited or easily treated (as in
bleeding from hemorrhoids or a urinary tract infection). However, in most
instances it will be necessary to rule out potentially remediable lesions. In
GI bleeding, patients may initially have either an upper or lower endoscopy.
Alternatively, patients may have an upper GI or barium enema radiographs.
Which tract to initially evaluate should be based on the patient's history. If
either the upper or lower tract evaluation reveals an abnormality, there is
generally no need to evaluate the other tract. In patients with hematuria and
pyuria, a urine culture should be performed to exclude a urinary tract
infection. If the urine is sterile, a renal ultrasound or an intravenous
pyelogram should be performed. If this is normal, a cystoscopy may reveal the
Emergent Reduction of the
There are conflicting
guidelines for administration of vitamin K in patients with an elevated PT/INR.
- If the PT/INR is
between 6.0- 10.0 and you think the patient's INR reflects a steady state
response (that is, not an overdose, not an acute drug interactions, not acute
hepatitis or CHF, etc.) and if there is no evidence of bleeding, warfarin can
simply be discontinued. (61)
- Assuming the patient is
at steady-state, the INR begins to fall approximately 30 hours after the
last dose of warfarin. The half-life of the INR varies from 0.5-1.2 days,
with older individuals having a longer half-life. Thus, for most high INRs
(7-10 range), the value will fall to ~ 3.0 an average of 72 hours after the
last dose of warfarin. Example: INR= 9.0 and warfarin is stopped. Thirty hours
later the INR will be ~9.0, 54 hours after discontinuation it will be 5.0, 78
hours after discontinuation it will be ~ 3.0, and 102 hours after
discontinuation it will be ~2.0. (40)
- If the INR is high
(7-10) and the patient is at high risk for bleeding or if you think the INR is
possibly rising because of a drug interaction or coexisting disease, or
error in warfarin dosing, vitamin K, 0.5 or 1.0 mg should be given
intravenously over 20 minutes. Twenty?four hours after administration the INR
should fall to a value near INR = 3.0 assuming the INR reflected a steady
state (and not, for example, an overdose of super warfarin, acute liver
failure etc.). Once the INR begins to fall, an adjusted lower dose of warfarin
can be given to the patients who need ongoing anticoagulation. (62)
- If the patient is
actively bleeding, intravenous vitamin K (any dose) should be given slowly
together with 3 units (jumbo pack) of fresh frozen plasma, which may need to
be repeated after 12-15 hours if the INR remains elevated.
Use of Warfarin During
Because warfarin is
teratogenic, all women of childbearing potential who are treated with warfarin
should be informed of its risk and be offered contraception. (9) If a patient
becomes pregnant, subcutaneously administered heparin should be substituted for
the remainder of the pregnancy. (63,64) Warfarin can be safely given to women
who breast feed their children.
Adverse Effects of
- Hemorrhage is the major
complication associated with warfarin therapy. (30) Rates of life threatening
bleeding are on the order of 0.5-1.0 events/ 100 patient-years and bleeding
that requires medical attention occurs at a rate of ~7-10 events/100 patient
years. Because one risk factor for bleeding is an excessively high PT/INR,
vigilance following the PT/INR is required.
- Warfarin induced skin
necrosis is a very rare complication seen in patients started on warfarin
without heparin; many of these patients have an underlying procoagulant
disorder such as protein C deficiency. Because warfarin reduces protein C
levels, it exacerbates this deficiency in the fibrinolytic system and
predisposes to thrombosis, which is manifest in small vessels in adipose
tissue. Rational treatment is fresh frozen plasma (providing protein C),
initiation of intravenous heparin and, at least temporary
discontinuation of warfarin.
- Some patients with
protein C & S deficiency have been successfully started on warfarin (gradually
increasing the dose) while on heparin therapy. (65)
- Other uncommon
complications include persisting diarrhea and alopecia. Use of a different
coumarin preparation (e.g. dicumerol) may be beneficial.
During Warfarin Therapy.
- Although recurrent
venous thromboembolism is a major problem, recurrence during adequate warfarin
therapy is rare. (66)
- When a patient who
is adequately anticoagulated develops symptoms of recurrent DVT, the
clinician should suspect either post-phlebitic swelling or recurrent
thrombosis despite adequate warfarin.
- A useful test to
exclude active thrombosis is to measure the plasma level of D-dimer (using an
ELISA test), which is elevated in over 95% of patients with venous
thromboembolism. A high level of D-dimer although not specific, raises the
possibility that the patient has a procoagulant disorder leading to the
thrombosis during warfarin therapy, particularly an underlying adenocarcinoma.
- Repeat venography or
ventilation-perfusion lung scanning may document recurrent thrombosis if a
baseline test was done.
- Serial real-time
ultrasound testing is less reliable in detecting recurrent ipsilateral clot
since neither the exact extent of thrombosis or clotting in collateral vessels
are usually reported.
- A common cause of
active thrombosis during adequate warfarin therapy is the presence of an
underlying malignancy (especially adenocarcinoma of pancreas, GI tract,
prostate, ovary, stomach and breast). If a malignancy is documented, heparin
should be substituted for warfarin since the latter is usually ineffective.
- In patients with
thrombosis and the Lupus-anticoagulant, a higher intensity of anticoagulation
may be required, i.e. INR= 3.0-4.0.(79) Serial D-dimer testing may be useful
to document effectiveness of warfarin in these patients. (71,72)
TABLE 1. HEPARIN DOSING
|| HIGH DOSE2
|AFTER 4 HOURS
||HOLD 1 HR. THEN
REPEAT APTT 4-6 HR.
REPEAT APTT q 6 HR.
BOLUS 80 U/KG
** BOLUS 40 U/KG
+ 1,240 U/HR. IF AT HIGH RISK FOR BLEED
$ BOLUS 5,000 U
# HOLD 30 MIN
## HOLD 60 MIN
1 Ann Int Med.
1993; 119:874-872. 2 Arch Int Med. 1992; 152:1589-1595.
3 Arch Int Med. 1991; 151:333-337.
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