Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti
G. Pharmacology and management of the vitamin K antagonists:
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition). Chest. 2008;133:160S–198S.
2] Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J,
Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH;
American College of Chest Physicians. Evidence-based
management of anticoagulant therapy: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest. 2012 Feb;141(2 Suppl):e152S-84S. doi:
are the current recommendations for INR monitoring as well as
the maximum interval between levels for stable patients?
-INR monitoring should begin after the 2nd or 3rd dose during
the initiation phase. Monitoring intervals should not exceed
4 weeks in stable patients. Ideally, anticoagulation therapy
should be managed in a "systematic and coordinated fashion,"
in order to ensure optimal therapy. This includes patient
education, follow-up and tracking activities.
|9th ACCP suggestions:
-Patients with consistently stable INRs: INR testing
frequency may be increased up to 12 weeks rather than
every 4 weeks (Grade 2B).
-Patients with previously stable therapeutic INRs who
have a single out-of-range INR of
0.5 below or above therapeutic range: (1)
continue current dose. (2) INR testing
within 1 to 2 weeks. (Grade 2C).
-Stable patients with a single subtherapeutic value
should NOT be routinely bridged with heparin.
-Routine use of vitamin K supplementation is not
recommended (Grade 2C) .
-If any changes occur that may alter the response to warfarin
such as the addition of new medications or herbal
supplements, changes in diet, etc., the monitoring frequency
should be increased until the patient is re-stabilized.
-Hospitalized patients: INR monitoring is usually performed
daily (starting after 2nd or 3rd dose) until a therapeutic
INR is achieved for at least 2 consecutive days. Then monitor
the INR 2-3x weekly x 1 - 2 weeks. Monitoring frequency
can be reduced further depending on the stability of the INR
are some of the challenges associated with warfarin dosing?
-Warfarin has a narrow therapeutic index (close monitoring
and individualized dosing schemes are essential).
-There is the potential for significant variability in the
response to warfarin based on several factors such as genetic
variance; diet; interacting medications; and co-existing
-Maintaining a therapeutic level/response requires a
coordinated effort and a good understanding of the
complexities associated with warfarin therapy. Patient
education is an integral component!
are the key pharmacokinetic/pharmacodynamic aspects of
-Warfarin is a racemic mixture (R & S enantiomers).
-Warfarin (racemic) half-life: 36 to 42 hours
-R-warfarin half-life: 45 hours
-S-warfarin half-life: 29 hours
-S-warfarin is 2.7 - 3.8 x more potent than R-warfarin
-The R & S enantiomers are metabolized by different
-S enantiomer primary metabolic enzyme (p450):
-R enantiomer primary metabolic enzymes (p450):
1A2 and 3A4.*
*Key to pharmacogenetic variablility.
-Warfarin is ~100% bioavailable (F=1).
-Highly water soluble.
-Rapidly absorbed from the GI tract.
-Peak blood conc. achieved in ~90 min (0.3 to 4 hrs) after
-Warfarin is highly protein bound (> 98%)
-Mechanism of action (package insert):
Warfarin acts by inhibiting the synthesis of vitamin
K-dependent clotting factors, which include Factors II, VII,
IX, and X, and the anticoagulant proteins C and S. Vitamin K
is an essential cofactor for the post ribosomal synthesis of
the vitamin K-dependent clotting factors. Vitamin K promotes
the biosynthesis of
acid residues in the proteins that are essential for
biological activity. Warfarin is thought to interfere with
clotting factor synthesis by inhibition of the C1 subunit of
vitamin K epoxide reductase (VKORC1) enzyme complex, thereby
reducing the regeneration of vitamin K1 epoxide.
-Warfarin's full antithrombotic effect is not achieved UNTIL
adequate reductions in prothrombin (factor II) occur and
possibly factor X. Early reductions in factors VII and IX
and the associated decreases in the INR do NOT represent the
full therapeutic effect of warfarin. (Review:
antithrombotic - anticoagulant dissociation. Anticoagulant
effects occur in ~2 days vs a minimum of 4-6 days for an
initial antithrombotic effect).
Full antithrombotic effect (peak effect): (5 - 7 days)
|Prothrombin (factor II)
||60 - 72
|The PT test responds to a reduction
of 3 of
the 4 vit K-dependent clotting factors (II,
VII, X). Rates of decline for each factor is
inversely proportional to its half-life. Factor
VII (half-life: 4-6 hrs) for example falls
precipitously initially (during the first few days of
warfarin therapy), and the PT reflects mainly a
reduction of factor VII initially. Subsequent
reductions in the PT are due to reductions in factors
X and II. Several days are required in order achieve
steady factor II levels (half-life: 62 - 70 hrs).
large loading doses ever recommended?
-A loading dose (dose > 10mg) is not recommended.
Initial dosages should be based on the patient's age, risk
factors for bleeding, and concomitant drug therapy.
A starting dose of 7.5 - 10mg may be suitable for a patient
with a low-risk for bleeding, while initial dosages of 2-3 mg
may be appropriate for high-risk patients.
|9th ACCP suggestion:
Patients healthy enough to be treated as outpatients:
Give warfarin 10 mg daily x 2 days. Further dosing
should be based on INR monitoring. (Preferred to
starting with an estimated maintenance dose.)
are some of the factors that may cause fluctuations in INR
(1) Inaccuracy in INR testing.
(2) Changes in vitamin K intake or absorption.
(3) Changes in warfarin absorption or metabolism.
(4) Changes in vitamin K-dependent coag factor synthesis or
(5) Changes in concomitant drug use
(6) Patient compliance.
do you handle elevated INR values?
-Management of elevated INRs:
-Minor elevations in the INR:
(a) managed by adjusting dose in increments of 5
to 20% based on the
(b) by more frequent monitoring (expectation that the
INR will return to
without a dosage change).
How do you handle
(1) Immediate correction of the INR is mandatory.
(2) FFP (fresh frozen plasma) can be given, HOWEVER,
"immediate and full correction can ONLY be achieved by the
use of factor concentrates because the amount of FFP required
to fully correct the INR is considerable and may take hours
to infuse. "
(a) One study found that a dose of 500 IU of
prothrombin complex concentrate was optimal for rapid
reversal for an INR of < 5.0 but that higher doses might be
needed for more elevated INRs.
(b) Recombinant factor VIIa (not FDA approved for this
indication) has been shown to be effective in varying doses
(10 ug/kg to maximum cumulative dose of 400 ug/kg) .
Vitamin K should be administered simultaneously (Factor VIIa
has a short half-life)
(c) "Recombinant factor VIIa also has been associated
with an increased risk of thromboembolic events, as have some
prothrombin complex concentrates." The possible risk versus
perceived benefit must be taken into account.
(d) Availability of these agents is a likely issue.
Many institutions do not
stock these preparations.
|9th ACCP suggestion: warfarin-associated
major bleeding: rapid reversal of anticoagulation
with four-factor prothrombin complex concentrate
(PCC) rather than with plasma. (Grade 2C) . Also
suggest additional use of vitamin K 5 to 10 mg
administered by slow IV injection rather than
reversal with coagulation factors alone (Grade 2C) .
Complex Concentrates (PCC) Comparison
(vial sizes: 500 IU - diluted with 20 ml sterile
water) - 25 units/ml.
Beriplex® P/N - CSL Behring
|280 - 760 IU
180 - 480 IU
360 - 600 IU
140 - 620 IU
140 - 640 IU
|380 - 800 IU
200 - 500 IU
400 - 620 IU
500 - 1020 IU
420 - 820 IU
240 - 680 IU
|Shelf-life: 2 years
||Shelf-life: 36 months
|Dosage for INR >3.5:
>1.9 ml/kg. Single dosages should not exceed 3000 IU
||Dosage for INR >6.0:
>2 ml/kg. Single dosages should not exceed 5000 IU
Risk exists for thromboembolic
Product is prepared from large pools
of human plasma, which may contain
the causative agents of hepatitis
and other viral diseases.
Risk exists for thromboembolic
do you manage patients with variable INRs not attributable to
any of the usual causes?
Patient may be started on low-dose vitamin K (100 to 200 ug)
orally once daily. Close
monitoring of the INR is necessary. Warfarin dosage must be
adjusted. (INR declines in response to vitamin K
1. Ansell J, Hirsh J, Hylek E, Jacobson A,
et al. Pharmacology and Management of the Vitamin K Antagonists:
American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest. 2008 (suppl 6);133:160s-198s.