Warfarin

Warfarin, sold under the brand name Coumadin among others, is used as an anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Warfarin may sometimes be prescribed following a ST-segment elevation myocardial infarction and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously.
The common side effect, a natural consequence of reduced clotting, is bleeding. Less common side effects may include areas of tissue damage, and purple toes syndrome. Use is not recommended during pregnancy. The effects of warfarin are typically monitored by checking prothrombin time every one to four weeks. Many other medications and dietary factors can interact with warfarin, either increasing or decreasing its effectiveness. The effects of warfarin may be reversed with phytomenadione, fresh frozen plasma, or prothrombin complex concentrate.
Warfarin decreases blood clotting by blocking vitamin K epoxide reductase, an enzyme that reactivates vitamin K₁. Without sufficient active vitamin K₁, the plasma concentrations of clotting factors II, VII, IX, and X are reduced and thus have decreased clotting ability. The anticlotting protein C and protein S are also inhibited, but to a lesser degree.
It is wrongly described as a "vitamin K antagonist". This term is incorrect. Warfarin does not antagonize the action of vitamin K1, but rather antagonizes vitamin K1 recycling, depleting active vitamin K1.
A few days are required for full effect to occur, and these effects can last for up to five days. Because the mechanism involves enzymes such as VKORC1, patients on warfarin with polymorphisms of the enzymes may require adjustments in therapy if the genetic variant that they have is more readily inhibited by warfarin, thus requiring lower doses.
Warfarin first came into large-scale commercial use in 1948 as a rat poison. It was formally approved as a medication to treat blood clots in humans by the U.S. Food and Drug Administration in 1954. In 1955, warfarin's reputation as a safe and acceptable treatment for coronary artery disease, arterial plaques, and ischemic strokes was bolstered when President Dwight D. Eisenhower was treated with warfarin following a highly publicized heart attack. It is on the World Health Organization's List of Essential Medicines. Warfarin is available as a generic medication and is sold under many brand names. In 2023, it was the 116th most commonly prescribed medication in the United States, with more than 5million prescriptions.

Medical uses

Warfarin is indicated for the prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism; prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Warfarin is used to decrease the tendency for thrombosis, or as secondary prophylaxis in those individuals who have already formed a blood clot. Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of embolism.
Warfarin is best suited for anticoagulation in areas of slowly running blood, and in blood pooled in dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation, the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism. Warfarin is also used in antiphospholipid syndrome. It has been used occasionally after heart attacks, but is far less effective at preventing new thromboses in coronary arteries. Prevention of clotting in arteries is usually undertaken with antiplatelet drugs, which act by a different mechanism from warfarin. It can be used to treat people following ischemic strokes due to atrial fibrillation, though direct oral anticoagulants may offer greater benefits.

Dosing

Dosing of warfarin is complicated because it is known to interact with many commonly used medications and certain foods. These interactions may enhance or reduce warfarin's anticoagulation effect. To optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by a blood test measuring an prothrombin time. During the initial stage of treatment, INR is checked daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose. Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient setting. Instead of a blood draw, the point-of-care test involves a simple finger prick.

Maintenance dose

Recommendations by many national bodies, including the American College of Chest Physicians, have been distilled to help manage dose adjustments.
The maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin K₁ in the diet. Keeping vitamin K₁ intake at a stable level can prevent these fluctuations. Leafy green vegetables tend to contain higher amounts of vitamin K₁. Green parts of members of the family Apiaceae, such as parsley, cilantro, and dill are extremely rich sources of vitamin K; cruciferous vegetables such as cabbage and broccoli, as well as the darker varieties of lettuces and other leafy greens, are also relatively high in vitamin K₁. Green vegetables such as peas and green beans do not have such high amounts of vitamin K₁ as leafy greens. Certain vegetable oils have high amounts of vitamin K₁. Foods low in vitamin K₁ include roots, bulbs, tubers, and most fruits and fruit juices. Cereals, grains, and other milled products are also low in vitamin K₁.
Several studies reported that the maintenance dose can be predicted based on various clinical data.

Self-testing

Anticoagulation with warfarin can also be monitored by patients at home. International guidelines on home testing were published in 2005. The guidelines stated:
A 2006 systematic review and meta-analysis of 14 randomized trials showed home testing led to a reduced incidence of complications, and improved the time in the therapeutic range.

Alternative anticoagulants

In some countries, other coumarins are used instead of warfarin, such as acenocoumarol and phenprocoumon. These have a shorter or longer half-life, and are not completely interchangeable with warfarin. Several types of anticoagulant drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran, apixaban, edoxaban, and rivaroxaban, have been approved in a number of countries for classical warfarin uses. Complementing these drugs are reversal agents available for dabigatran, and for apixaban, and rivaroxaban. Andexanet alfa is suggested for edoxaban, but use of it is considered off label due to limited evidence. A reversal agent for dabigatran, apixaban, edoxaban, and rivaroxaban is in development.

Contraindications

All anticoagulants are generally contraindicated in situations in which the reduction in clotting that they cause might lead to serious and potentially life-threatening bleeds. This includes people with active bleeding conditions, or disease states with increased risk of bleeding. For patients undergoing surgery, treatment with anticoagulants is generally suspended. Similarly, spinal and lumbar puncture carry increased risk, so treatment is suspended prior to these procedures.
Warfarin should not be given to people with heparin-induced thrombocytopenia until platelet count has improved or normalised. Warfarin is usually best avoided in people with protein C or protein S deficiency, as these thrombophilic conditions increase the risk of skin necrosis, which is a rare but serious side effect associated with warfarin.

Pregnancy

Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal death, and preterm birth. Coumarins are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin in utero appears to be around 5%, although higher figures have been reported in some studies. Depending on when exposure occurs during pregnancy, two distinct combinations of congenital abnormalities can arise.

First trimester of pregnancy

Usually, warfarin is avoided in the first trimester, and a low-molecular-weight heparin such as enoxaparin is substituted. With heparin, risks of maternal haemorrhage and other complications are still increased, but heparins do not cross the placental barrier, so do not cause birth defects. Various solutions exist for the time around delivery.
When warfarin is given during the first trimester—particularly between the sixth and ninth weeks of pregnancy—a constellation of birth defects known variously as fetal warfarin syndrome, warfarin embryopathy, or coumarin embryopathy can occur. FWS is characterized mainly by skeletal abnormalities, which include nasal hypoplasia, a depressed or narrowed nasal bridge, scoliosis, and calcifications in the vertebral column, femur, and heel bone, which show a peculiar stippled appearance on X-rays. Limb abnormalities, such as brachydactyly or underdeveloped extremities, can also occur. Common nonskeletal features of FWS include low birth weight and developmental disabilities.

Second trimester and later

Warfarin administration in the second and third trimesters is much less commonly associated with birth defects, and when they do occur, are considerably different from FWS. The most common congenital abnormalities associated with warfarin use in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye defects. Because of such later pregnancy birth defects, anticoagulation with warfarin poses a problem in pregnant women requiring warfarin for vital indications, such as stroke prevention in those with artificial heart valves.
Warfarin may be used in lactating women who wish to breastfeed their infants. Available data does not suggest that warfarin crosses into the breast milk. Similarly, INR levels should be checked to avoid adverse effects.