Warfarin, to load or not
Warfarin is an oral anticoagulant
frequently used to treat or prevent various thromboembolic
events or diseases associated with substantial risk of thromboembolism.
In 2001, it was listed among
the top 100 selling prescription drugs in the United States.
Despite this volume of prescription sales, there remains confusion
about the appropriate management of warfarin dosing, particularly
in regards to initiating patients na´ve to oral anticoagulant
therapy. Discrepancies exist in clinical practice on initiation
of warfarin therapy utilizing a loading dose (10 mg or greater
for 2 or more days) versus initiation at average daily maintenance
doses (5 mg). This may be due to a lack of understanding about
warfarin's pharmacology or mechanism of action and to the
limited published literature that addresses this issue.
Warfarin works through antagonism
of the vitamin K oxidation system. The liver uses oxidized
vitamin K in the synthesis of clotting factors VII, IX, X
and II. This interference with vitamin K oxidation results
in an inhibition of the factor synthesis process and anticoagulation
is ultimately achieved after clearance of the currently active
clotting factors occurs. The half-life of activated clotting
factors varies from 6 hours (factor VII) to 50 hours (factor
II). This means that initial changes in the international
normalized ratio (INR) can be seen in as little as 24-36 hours,
with depletion of activated factor VII, and full antithrombotic
effects are seen in 5-7 days, as activated factor II is depleted.
Warfarin has both anticoagulant
and antithrombotic properties. Anticoagulation is achieved
when therapeutic INRs are attained (an INR between 2-3 is
considered therapeutic in most instances), which can occur
within 1-3 days after therapy initiation. However, recall
that these changes reflect depletion of Factor VII. This means
that sufficient concentrations of activated Factor IX, X and
II remain and are able to propagate clot formation. The ability
of warfarin to inhibit clot expansion or development, or its
antithrombotic effect, is achieved after clearance of Factor
II (prothrombin). Thus, therapeutic INRs within the first
few days after warfarin initiation do not equal clinical effectiveness,
particularly in the case of management of acute thromboembolic
events. This delayed effect on prothrombin is the reason for
concomitant heparin therapy during the first 4-5 days of warfarin
therapy regardless of attainment of a therapeutic INR.
In addition to synthesis of
clotting factors, oxidized vitamin K is used in the production
of proteins C and S, our endogenous anticoagulants. Thus,
warfarin therapy also inhibits production of these proteins.
Protein C has a half-life of only about 8 hours and is there
fore depleted rather quickly after initiation of warfarin
therapy. This in turns leads to the development of a hypercoaguable
state resultant from this depletion of endogenous anticoagulants
with persistent activity of endogenous clotting factors.
warfarin with loading doses of 10 mg per day or more should
lead to INR values within the therapeutic range more quickly
than daily doses of 5 mg. This may very well be the case,
and in fact, this does often occur, but we know that therapeutic
INRs within the first few days of warfarin therapy do not
translate into clinical effectiveness for antithrombosis.
In addition, using loading doses of warfarin could potentiate
hypercoaguability with rapid effects on proteins C and S.
The full effects of loading doses will not be observed until
days 5-7 after initiation. This means that a therapeutic INR
on day 2 could be a supratherapeutic INR (> 3.0 or >3.5
depending on indication) on day 5 and may put the patient
at increased risk for bleeding complications. Some studies
have been published in the medical literature that addresses
In the late 1960's, O'Reilly
and colleagues examined the effects of weight based loading
doses of warfarin (1.5 mg/kg of body weight), compared to
once daily doses of 10 or 15 mg, on prothrombin time and plasma
concentrations of factors VII, IX, X, and II. Thirty- two
otherwise healthy subjects were given a one time loading dose
of 1.5 mg/kg and observed for 120 hours. The average warfarin
dose administered was about 100 mg. Effect on prothrombin
time was reported as a percentage of normal prothrombin complex
activity. A therapeutic range was considered to be <35%
of normal activity. By 36 hours, all subjects had prothrombin
complex activity <35% of normal with maximal effects seen
at 48 hours that persisted throughout the observation period.
In a second series of study the same population was divided
into 2 groups of 15 subjects each and received either 10 or
15 mg of warfarin a day. These subjects were observed for
at least 120 hours. In the 10 mg per day group, the mean prothrombin
complex activity was 36% of normal by day 5 and 32% of normal
by day 6. In the 15 mg per day group, mean activity fell to
28% of normal by day 4. The authors then concluded that a
single weight based loading dose of warfarin lead to therapeutic
effects on prothrombin time significantly more quickly than
either the 10 or 15 mg per day doses. However, when comparing
the effect on percent change in plasma clotting factors in
6 subjects they found that there was only a statistically
significant difference in the change of Factor VII at 24 and
48 hours. Percent change in concentration of Factors IX, X,
and II were similar for both the groups receiving the 1.5
mg/kg dose or the 15 mg/day dose at all time periods of observation.
This then appears that the more rapid changes seen in prothrombin
complex activity may be related to decreased concentrations
of Factor VII and not to changes in Factor IX, X, or II. Therefore
the question still remains whether or not this large load
produces a clinically significant therapeutic response at
Harrison and colleagues conducted
a randomized clinical trial to compare the effects of 5 and
10 mg loading doses of warfarin. They used laboratory markers
(time to reduction in levels of Factor II and X, and protein
C) as indicators of both safety and efficacy. Other outcome
measures included time needed to reach INR values in the therapeutic
range (2.0-3.0) and percentage of supratherapeutic INRs (>3.0).
Fifty-one patients were enrolled and randomly assigned to
receive either 5 or 10 mg warfarin loading doses for the first
2 consecutive days of therapy. After that time, warfarin dosing
was adjusted using a nomogram. The 2 groups were similar in
respect to baseline characteristics with 25 and 24 people
in the 10 mg and 5 mg groups, respectively. There was a statistically
significantly greater number of people in the 10 mg group
with therapeutic INRs (>2.0) at 36 hours as compared to
the 5 mg group (44% vs. 8% respectively, P = 0.005). However,
at 60 hours none of the persons in the 5 mg group had supratherapeutic
INRs, which was significantly less than in the 10 mg group
(36%, P = 0.002). There were no bleeding events noted for
either group. Similar to the findings by O'Reilly, levels
of Factor II and X gradually decreased with no significant
differences between the groups; while Factor VII and protein
C levels decreased quickly and were significantly lower in
the 10 mg group at both 36 and 60 hours. These findings do
not support the use of loading doses of 10 mg or more as antithrombotic
effects were reached in similar periods in both groups despite
quicker attainment of a therapeutic INR in the 10 mg group.
Another group of investigators,
headed by Crowther, also compared effects of 5 and 10 mg loading
doses of warfarin in a prospective, randomized clinical trial.
Their goal was to assess the ability of the dosing strategies
to achieve a stable INR between 2.0-3.0 within the first 5
days of therapy. The primary endpoint was the proportion of
people with therapeutic INR values for 2 consecutive days
and whose INR did not exceed 3.0. Like patients in Harrison's
study, these patients received the loading doses on days 1
and 2 and thereafter dosing was adjusted using an algorithm.
Fifty-three persons were enrolled (32 in the 5 mg group, 21
in the 10 mg group). A larger percentage of people in the
5 mg group reached the primary endpoint (66%) as compared
to the 10 mg group (24%, P <0.003). Additionally, there
was a greater incidence of supratherapeutic INRs (>3.0)
by study day 4 in the 10 mg group (24% vs. 7%, P = 0.11).
These studies share one common
limitation, small sample size. Also, in none of the studies
do the authors comment on whether or not their studies were
designed with sufficient power to detect the differences that
they did between groups. However, when considering that similar
results were seen in these trials, for both INR outcomes and
change in levels of clotting factors, they do offer some evidence
to help answer our question regarding warfarin loading and
support the current Chest Guideline recommendation. This recommendation
is that initiation of warfarin using loading doses is unnecessary
as a therapeutic INR can be achieved in 4-5 days in most cases
when beginning with 5 mg a day dosing. In addition, keep in
mind that certain patients may be more sensitive to the effects
of warfarin, like those with liver disease, malnutrition,
or the elderly. These patients may even require initial doses
less than 5 mg per day. Also, it is prudent to comment that
persons with a history of warfarin use with higher than average
maintenance dosing requirements may need initiation at doses
greater than 5 mg per day in order to achieve effective antithrombosis
in a reasonable time frame.
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