Warfarin

Introduction

Warfarin use can be challenging in clinical settings due to

  • Its narrow therapeutic range
  • The influence of various factors on dosing such as genetic variation, drug interactions and diet.

The time spent outside the therapeutic range increases the risk of bleeding and/or thromboembolic complications that warfarin is intended to prevent.



Baseline Testing

Before initiating warfarin therapy, certain baseline tests should be obtained

  • Baseline prothrombin time (PT) with international normalized ratio (INR) and baseline activated partial thromboplastin time (aPTT)
  • Complete blood count (CBC) including platelet count, to obtain a baseline and identify thrombocytopenia.
  • Serum creatinine, to estimate glomerular filtration rate (GFR)
  • Liver function tests, to identify potential alterations of warfarin metabolism
  • Urine (or serum) pregnancy test for women of childbearing potential (due to risk of teratogenicity).



International Normalized Ratio (INR) Goals

International Normalized Ratio (INR) is a blood test that measures how long it takes for your blood to clot.

  • For normal patients who are not on anticoagulation, the INR is usually 1.0.
  • A higher INR means your blood is clotting more slowly and at an increased risk of bleeding.

The INR goals for warfarin therapy typically range from 2 to 3 for patients with atrial fibrillation or venous thromboembolism and somewhat higher for patients with mechanical heart valves.

Warfarin INR Targets



Warfarin Dosing

Initial dosing

  • An initial daily dose of ≤5 mg is suggested, unless the patient is known from previous experience to require higher doses.
  • Lower starting dose (≤3 mg/day) is recommended for patients who may be sensitive to warfarin such as
    • In elderly patients or in patients who are debilitated,
    • Malnourished,
    • Have CHF,
    • Have liver disease,
    • Have had recent major surgery, or
    • Are taking medications known to increase the sensitivity to warfarin (e.g., amiodarone)
  • Higher doses or loading dose (≥10 mg) generally do not result in more rapid therapeutic anticoagulation, but may increase the risk of supratherapeutic INR and bleeding.
  • An initial effect on the INR usually occurs within the first 2-3 days [due to depletion of factor VII, but there are other vitamin K–dependent clotting factors with longer half-lives (e.g., factors II, IX, and X) which must also be depleted]. A therapeutic INR can usually be achieved within 5-10 days.
    • In situations where a rapid effect is required, low-molecular-weight heparin (LMWH) should be administered concurrently with warfarin. LMWH usually can be discontinued in 5-6 days or after 2 consecutive therapeutic INR values are achieved.

INR-based Initial Dose Adjustment

  • Typically, the PT with international normalized ratio (INR) is measured daily in hospitalized patients and starting on or around day 3 in healthy outpatients. Dosing on day 3 and subsequent days is based on the previous PT and INR results.

Warfarin Initiation and Frequency of INR

Establishing a Maintenance Dose

  • Maintenance doses of warfarin vary significantly from patient to patient, ranging from <2 mg to ≥10 mg per day, and are based on PT/INR readings.
  • Warfarin dosing should be calculated using weekly dosing.
    • Dose can be increased or decreased up to 15% of weekly dosing.
    • According to ICSI guideline, increase of 15% weekly dose would correspond to increase in INR of 1.0. Locally, for simplicity, we use 1% increase in warfarin weekly dose correspond to increase in INR of 0.1.
  • The effect of dose changes may take up to 3 days to be reflected in the PT/INR.
    • Thus, significant dose changes generally should be made only based on PT/INR results obtained at least 2 days after a previous dose adjustment.



Administration Time

Clinicians often tell patients to take warfarin in the evening to allow same-day dose corrections based on INR results.



Poor INR Control

2 major factors that may lead to poor control of warfarin dosing are

  • Medication adherence
    • Failure to take warfarin appropriately
  • Very low dietary vitamin K intake/vitamin K deficiency
    • May make the patient especially sensitive to small day-to-day variations in vitamin K intake.



Counselling and Patient Education

Tell your doctor immediately if you have any unexplained bruising, bleeding, pink, red or dark brown urine, or red or black faeces.

Patients are advised to maintain a relatively consistent level of intake rather than told to avoid vitamin K-containing foods.

Warfarin has numerous drug interactions that may warrant a change in therapy or increased PT/INR monitoring.

  • It is important to tell your doctor about all of the medications you are taking, including over-the-counter medications, before starting warfarin.

Possibility of variable INR control with excessive alcohol intake or "binge" drinking.

Tobacco may affect warfarin efficacy, especially smokeless tobacco, which has a high vitamin K content.

Avoid sport activities which are aggressive because use of an anticoagulant is associated with an increased risk of trauma-associated bleeding.

Warfarin is a known teratogen and is generally contraindicated during at least the first trimester of pregnancy.



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