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Management of elevated INR's - Vitamin K dosing

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1]  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: 10.1378/chest.11-2295.
What 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 leq 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 results.
What 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 disease state(s).

-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!  
What are the key pharmacokinetic/pharmacodynamic aspects of warfarin?

Key facts:
-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 pathways
              -S enantiomer primary metabolic enzyme (p450): CYP2C9.*
              -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 oral administration.

-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 gamma-carboxyglutamic 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.

Antithrombotic effect
-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)

Protein Half-life (Hours)
Prothrombin (factor II) 60 - 72
Factor VII 4-6
Factor IX 20-30
Factor X 24–40
Protein C 8-10
Protein S 40 -60
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).

Are 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.)   (Grade 2C)
What are some of the factors that may cause fluctuations in INR values?

(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 metabolism
(5) Changes in concomitant drug use
(6) Patient compliance.
How 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
           cumulative weekly dose or 
     (b) by more frequent monitoring (expectation that the INR will return to
           therapeutic levels without a dosage change).

How do you handle life-threatening bleeding?
(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) .

Prothrombin Complex Concentrates (PCC) Comparison
(vial sizes: 500 IU - diluted with 20 ml sterile water) - 25 units/ml.
Octaplex®  -Octapharma Beriplex® P/N - CSL Behring
Factor II
Factor VII
Factor IX
Factor X
Protein C
Protein S
280 - 760 IU
180 - 480 IU
500 IU
360 - 600 IU
140 - 620 IU
140 - 640 IU
Factor II
Factor VII
Factor IX
Factor X
Protein C
Protein S
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 (120 ml). Dosage for INR >6.0:  >2 ml/kg. Single dosages should not exceed 5000 IU (200 ml).
Risk exists for thromboembolic episodes.  

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 episodes.
How 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 administration).


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.

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