Mechanism of action: Warfarin interrupts the synthesis of clotting factors II, VII, IX, and X, and proteins C and S. Synthesis and activation of these clotting factors and proteins requires the reduced form of vitamin K, and reduced vitamin K is produced by the activity of the enzyme vitamin K epoxide reductase complex 1 (VKORC1).
- inhibits the activity of VKORC1, deleting vitamin K stores
- prevents hepatic synthesis of the clotting factors and proteins
- reduces the activity of circulating clotting factors and proteins.
Warfarin is often referred to as a vitamin K antagonist, but warfarin does not actually antagonize vitamin K.
At therapeutic doses, warfarin decreases the functional amount of each vitamin K–dependent coagulation factor by 30%–70%. Warfarin has no effect on the activity of fully γ-carboxylated factors already in the circulation, and these must be cleared before it can produce an anticoagulant effect.
Warfarin does not dissolve an existing thrombus; It prevents new thrombi from forming and prevents the extension of an existing thrombus.
Onset of effects: A measurable effect of warfarin, reflected by an increase in INR, can be seen within 24-72 hours. However, the half-life of some of the clotting factors is quite long, e.g., 60-72 hours for factor II, so complete anti-coagulation and full therapeutic effect require 5-7 days of warfarin therapy.
Duration of effects: Two to 5 days.
Warfarin is given orally once a day. IV warfarin is no longer produced.
- Prophylaxis and treatment of thromboembolic disorders and embolic complications caused by atrial fibrillation or cardiac valve replacement.
- After an MI, as an adjunct to reduce the risk of systemic embolism that may cause another MI or a stroke.
Warfarin is also used off-label for preventing TIAs in patients who have atrial fibrillation, rheumatic mitral valve disease, or a mechanical prosthetic heart valve.
Dose: Warfarin dosing is a balance between:
- Attaining a level of anticoagulation that will prevent thrombus formation and embolic events
- Maximizing the amount of time when the patient is in the therapeutic range in order to minimize the amount of time the patient is at risk for thrombus formation and embolic events
- Avoiding a level of anticoagulation that puts the patient at risk for bleeding
Before starting treatment with warfarin, a CBC, INR, aPTT, PT, serum creatinine, and liver function tests should be measured. (Note: The effect of hepatic and renal function on warfarin will be discussed later in this section).
The usual dose of warfarin is 2-5 mg a day during the initiation phase of 2-4 days, followed by 1-10 mg a day during the maintenance phase. The INR results determine the maintenance dose, and lower and higher starting and maintenance doses are used (Hull et al., 2019).
Warfarin dosing and INR monitoring are very individualized. An effective and safe dose depends on many factors, including age, bleeding history, co-morbidities, diet, drug interactions, genetic variability that affects the patient’s response to the drug, and the INR results. When and how often to measure the INR and what the INR should be will differ from patient to patient. Dosing algorithms are available, and they can be effective for starting and maintaining warfarin therapy and maximizing the time the patient is within the therapeutic range (Hull et al., 2019).
A typical approach is to measure the INR after the second day of taking warfarin and to decrease/increase the dose after that as needed. In most cases, an INR of 2-3 is the goal, but a higher INR is desired (Hull et al., 2019).
Adverse effects: Bleeding is the most common adverse effect. The risk for major bleeding, i.e., gastrointestinal, intracranial, and spinal, has been estimated to be from 0-2% a year. Factors that increase the risk of bleeding from warfarin are listed below. Several of these will be discussed in detail in the clinical Issues section.
- Advanced age
- Alcohol abuse, substance abuse
- Genetic differences in warfarin metabolism
- Hepatic impairment
- Kidney disease
- Labile INR
- Medications that affect coagulation
- Prior bleeding events
- Stroke or TIA